Big science: The cancer genome challenge

[Courtesy: NatureNews]

Databases could soon be flooded with genome sequences from 25,000 tumours. Heidi Ledford looks at the obstacles researchers face as they search for meaning in the data.

Heidi Ledford

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When it was first discovered, in 2006, in a study of 35 colorectal cancers¹, the mutation in the gene IDH1 seemed to have little consequence. It appeared in only one of the tumours sampled, and later analyses of some 300 more have revealed no additional mutations in the gene. The mutation changed only one letter of IDH1, which encodes isocitrate dehydrogenase, a lowly housekeeping enzyme involved in metabolism. And there were plenty of other mutations to study in the 13,000 genes sequenced from each sample. "Nobody would have expected IDH1 to be important in cancer," says Victor Velculescu, a researcher at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, who had contributed to the study.
But as efforts to sequence tumour DNA expanded, the IDH1 mutation surfaced again: in 12% of samples of a type of brain cancer called glioblastoma multiforme², then in 8% of acute myeloid leukaemia samples³. Structural studies showed that the mutation changed the activity of isocitrate dehydrogenase, causing a cancer-promoting metabolite to accumulate in cells⁴. And at least one pharmaceutical company — Agios Pharmaceuticals in Cambridge, Massachusetts — is already hunting for a drug to stop the process.
Four years after the initial discovery, ask a researcher in the field why cancer genome projects are worthwhile, and many will probably bring up the IDH1 mutation, the inconspicuous needle pulled from a veritable haystack of cancer-associated mutations thanks to high-powered genome sequencing. In the past two years, labs around the world have teamed up to sequence the DNA from thousands of tumours along with healthy cells from the same individuals. Roughly 75 cancer genomes have been sequenced to some extent and published; researchers expect to have several hundred completed sequences by the end of the year.

Click to enlarge.ADAPTED FROM M. R. STRATTON, P. J. CAMPBELL & P. A. FUTREAL

The efforts are certainly creating bigger haystacks. Comparing the gene sequence of any tumour to that of a normal cell reveals dozens of single-letter changes, or point mutations, along with repeated, deleted, swapped or inverted sequences (see 'Genomes at a glance'). "The difficulty," says Bert Vogelstein, a cancer researcher at the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, "is going to be figuring out how to use the information to help people rather than to just catalogue lots and lots of mutations". No matter how similar they might look clinically, most tumours seem to differ genetically. This stymies efforts to distinguish the mutations that cause and accelerate cancers — the drivers — from the accidental by-products of a cancer's growth and thwarted DNA-repair mechanisms — the passengers. Researchers can look for mutations that pop up again and again, or they can identify key pathways that are mutated at different points. But the projects are providing more questions than answers. "Once you take the few obvious mutations at the top of the list, how do you make sense of the rest of them?" asks Will Parsons, a paediatric oncologist at Baylor College of Medicine in Houston, Texas. "How do you decide which are worthy of follow up and functional analysis? That's going to be the hard part."

Drivers wanted

Click to enlarge.

Because cancer is a disease so intimately associated with genetic mutation, many thought it would be amenable to genomic exploration through initiatives based on the collaborative model of the Human Genome Project. The International Cancer Genome Consortium (ICGC), formed in 2008, is coordinating efforts to sequence 500 tumours from each of 50 cancers. Together, these projects will cost in the order of US$1 billion. Eleven countries have already signed on to cover more than 20 cancers (see map). The ICGC includes two older, large-scale projects: the Cancer Genome Project, at the Wellcome Trust Sanger Institute near Cambridge, UK, and the US National Institutes of Health's Cancer Genome Atlas (TCGA). The Cancer Genome Project has churned out more than 100 partial genomes and roughly 15 whole genomes in various stages of completion, and intends to tackle 2,000–3,000 more over the next 5–7 years. TCGA, meanwhile, wrapped up a three-year, three-cancer pilot project last year, then launched a full-scale endeavour to sequence up to 500 tumours from each of more than 20 cancers over the next five years.
Although the groups collaborate, TCGA has not yet been able to fully join the ICGC owing to differences in privacy regulations governing access to genome data. For now, members of both consortia are sequencing a subset of tumour samples from each cancer type — around 100 — and will follow this by sequencing promising areas in the remaining 400. That's useful, says Joe Gray, a cancer researcher at Lawrence Berkeley National Laboratory in California, but it's just a start. "In the early days, I thought that doing a few hundred tumours would probably be sufficient," he says. "Even at the level of 1,000 samples, I think we're probably not going to have the statistics we want."

“Even at the level of 1,000 samples, I think we're probably not going to have the statistics we want.”

What bigger numbers could provide is more driver mutations like the one in IDH1. These could, researchers argue, provide the clearest route to developing new cancer therapies. Many scientists have looked for mutations that occur repeatedly in a given type of tumour. "If there are lots and lots of abnormalities of a particular gene, the most likely explanation is often that those mutations have been selected for by the cancers and therefore they are cancer-causing," says Michael Stratton, who co-directs the Cancer Genome Project. This approach has worked well in some cancers. For example, with a frequency of 12%, it is clear that the IDH1 mutation is a driver in glioblastoma. Such searches should be fruitful for cancers that have fewer mutations overall. The full genome sequence of acute myeloid leukaemia cells yielded just ten mutations in protein-coding genes, eight of which had not previously been linked with cancer⁵.
Other cancers have proved more challenging. IDH1 was overlooked at first, on the basis of the colorectal cancer data alone. It was not until the search was expanded to other cancers that its importance was revealed. Moreover, some mutations shown to be drivers haven't turned up as often as expected. "It's very clear, now that all the genes have been sequenced in this many tumours, you have drivers that are mutated at very low frequency, in less than 1% of the cancers," says Vogelstein. To find these low-frequency drivers, researchers are sampling heavily — sequencing 500 samples per cancer should reveal mutations that are present in as few as 3% of the tumours. Although they may not contribute to the majority of tumours, they may still have important biological lessons, says Stratton. "We need to know about these to understand the overall genomic landscape of cancer."
Another popular approach has been to look for mutations that cluster in a pathway, a group of genes that work together to carry out a specific process, even if the mutations strike it at different points. In an analysis of 24 pancreatic cancers⁶, for instance, Vogelstein and his colleagues identified 12 signalling pathways that had been altered. Nevertheless, Vogelstein cautions that this approach is not easy to pursue. Many pathways overlap, and their boundaries are unclear. And because many have been defined using data from different animals or cell types, they do not always match what's found in a specific human tissue. "When you layer on top of that the fact that the cancer cell is not wired the same as a normal cell, that raises even further difficulties," says Vogelstein.

How much is enough?

Click to enlarge.

Separating drivers from passengers will become even more difficult as researchers move towards sequencing entire tumour genomes. To date, only a fraction of the existing cancer genomes are complete sequences. To keep costs low, most have covered only the exome, the 1.5% of the genome that directly codes for protein and is therefore the easiest to interpret. Assigning importance to a mutation found in the murky non-protein-coding depths of the genome will be more challenging, especially given that scientists don't yet know what function — if any — most of these regions usually serve. The vast majority of mutations fall here. The full genome sequence of a lung cancer cell line, for example, yielded 22,910 point mutations, only 134 of which were in protein-coding regions (see graphic, right)⁷. Nevertheless, finding them is worth the cost and effort, argues Stratton. "It could be that none of those mutations pertain to the causation of cancer," he says. "But it equally could be that some do. We'll never find out unless we systematically investigate."
Not everyone agrees. Some researchers argue that the costs of cancer-genome projects currently outweigh the benefits. Prices are poised to drop dramatically in the next few years as a new generation of sequencing machines comes online, says Ari Melnick, a cancer researcher at Weill Cornell Medical College in New York. "Why not wait for that?" he asks. In the meantime there are lower-hanging fruit to pick, says Stephen Elledge, a geneticist at Harvard Medical School in Boston, Massachusetts. Mutations that affect how many copies of a gene are found in a genome, he argues, are cheaper to assess and provide a more intuitive insight into biological processes. "If you delete something, you can turn a pathway off very efficiently," he says. "And if you amplify something, you can increase flow through the pathway. Making point mutations in genes to activate them is a little dicier."
Changes in gene copy number can be detected using fast, relatively inexpensive array-based technologies, but sequencing can provide a higher-resolution snapshot of these regions, says Elaine Mardis, a sequencing specialist at Washington University in St Louis, Missouri. Sequencing can enable researchers to map the boundaries of insertions and duplications with more precision and to catch tiny duplications or deletions that might have gone undetected by an array. Mardis, along with her colleague Richard Wilson and others, used sequencing to detect overlapping deletions in a breast cancer that had spread to other parts of the body (see page 999)⁸. The deletions spanned the region containing CTNNA1, a gene thought to suppress the spread, or metastasis, of cancer.
Meanwhile, cancer genomics is spreading out from under the large, centralized projects. For example, a $65-million, three-year paediatric-cancer genome project headed by researchers at St Jude Children's Research Hospital in Memphis, Tennessee, and Washington University aims to sequence 600 tumours. And more small projects seem poised to pop up. "Pretty much any cancer centre with any interest in the genomics of cancer is now buying these sequencers and using them," says Sam Aparicio, a cancer researcher at the University of British Columbia in Vancouver, Canada.

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Part of the reason that cancer-genome proponents don't want to wait for sequencing costs to drop is that the real work starts after the sequencing is over. As Velculescu puts it, "Ultimately it's going to take good old-fashioned biology and experimental analyses to really determine what these mutations are doing." With this in mind, the US National Cancer Institute established two 2-year projects in September last year to develop high-throughput methods to test how the mutations identified by the TCGA pilot project affect cell function. The two centres — one at the Dana-Farber Cancer Center in Boston, and another at Cold Spring Harbor Laboratory in New York — aim to systematize the way that researchers pull other needles like the IDH1 mutation from the cancer-genomes haystack and make sense of them. The Boston team will systematically amplify and reduce the expression of genes of interest in cell cultures, and the Cold Spring Harbor centre will study cancer-associated mutations using tumours transplanted into mice.

“It's going to take good old-fashioned biology to really determine what these mutations are doing.”

In addition, large-scale projects are being run in parallel with the cancer-sequencing consortia to assess the effects of deleting each gene in the mouse genome, enabling researchers to learn more about the normal function of genes that are mutated in cancer. Sequencing is all very well, researchers have realized, but it won't be enough. "Some people say statistics should get us all the drivers that are worthwhile," says Lynda Chin, an investigator with TCGA at Harvard Medical School. "I don't agree with that. At the end of the day, we need these functional studies to prioritize the list of potential cancer-relevant candidates." 

See also News and Views, page 989.

• References

  1. Sjöblom, T. et al. Science 314, 268-274 (2006). | Article | PubMed | ISI | ChemPort |
  2. Parsons, D. W. et al. Science 321, 1807-1812 (2008). | Article | PubMed | ChemPort |
  3. Mardis, E. R. et al. N. Engl. J. Med. 361, 1058-1066 (2009). | Article | PubMed | ChemPort |
  4. Dang, L. et al. Nature 462, 739-744 (2009). | Article | PubMed | ChemPort |
  5. Ley, T. J. et al. Nature 456, 66-72 (2008). | Article | PubMed | ChemPort |
  6. Jones, S. et al. Science 321, 1801-1806 (2008). | Article | PubMed | ChemPort |
  7. Pleasance, E. D. et al. Nature 463, 184-190 (2010). | Article | PubMed | ChemPort |
  8. Ding, L. et al. Nature 464, 999-1005 (2010). | Article

Studies spot a gene that allows some cancer cells to evade drugs such as Taxol.

By Cassandra Willyard

Ovarian cancer cells can survive chemotherapy drugs if they have defects in the FBW7 gene.STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY

Potent chemotherapy drugs such as Taxol (paclitaxel) prompt cancer cells to self-destruct — but some tumours stubbornly survive the treatment.
Two studies have now independently pinpointed a gene that lies behind at least part of this resistance^1,2. The discovery could help oncologists predict which patients are likely to respond to Taxol and drugs with similar actions, and which may not. It also flags up new targets for cancer therapy.
Taxol belongs to a class of chemotherapy drugs that work by binding to tubulin, a key protein in the network of filaments that maintains a cell's structure. Cells hit with anti-tubulin drugs "try to divide but they can't", says Ingrid Wertz, a molecular biologist at biotechnology company Genentech, headquartered in San Francisco, California.
Cancer cells that respond to Taxol eventually die. But other cells resist the treatment. In 2007, Wertz and her colleagues began asking why. The team found that, in responding cells, levels of one protein in particular, MCL1 – part of a family of proteins already known to affect a cell's life-cycle – were markedly lower immediately after treatment with Taxol (and with another anti-tubulin drug, vincristine). Further experiments showed that a known cancer-fighting protein, FBW7, was destroying MCL1.
Defects in the FBW7 gene had already been linked to a variety of cancers, including breast and colon. Wertz reasoned that its absence might in particular lead to high levels of MCL1, and explain why some cancer cells don't die when treated with anti-tubulin drugs.
Sure enough, the researchers observed that ovary and colon tumour cells with mutations in FBW7 had higher levels of the MCL1 protein and were more resistant to anti-tubulin drugs than cells with working copies of the gene.

Different route, same outcome

Meanwhile, Wenyi Wei, a molecular biologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts, and his colleagues were also studying FBW7's effects. Wei's group was focusing on a particular disease: T-cell acute lymphoblastic leukaemia (T-ALL), in which an estimated 30% of all cases have cells with FBW7 defects. These cells had high levels of other proteins that normally induce cell death, and yet they did not die. Wei's research into why that was led him to the same explanation: without the FBW7 protein, the cells did not break down MCL1, a necessary step for their death. "We went about it in opposite ways but ended up at the same conclusion," Wertz says, "which was really cool."
Wei and his colleagues also found a link to drug resistance. They exposed T-ALL cells to ABT-737, an experimental drug discovered by US healthcare firm Abbott, based in Abbott Park, Illinois (a newer version, ABT-263, is now in phase II clinical trials). This drug does not attack tubulin, but kills by blocking other proteins that promote cell survival. Again, cells with an FBW7 defect, and high levels of MCL1, are less sensitive to the drug. But the researchers found a way to solve this problem: by treating the cells with an agent called sorafenib, which lowered MCL1 levels and restored cells' sensitivity to the experimental drug.
The studies suggest that oncologists may be able to tailor their treatments based on whether or not patients have a defective FBW7 gene in tumour cells. "I think it has potential implications for any cancer in which these anti-microtubule agents are used," Wertz says.
Still, there are other ways to resist Taxol and similar drugs. Cancer cells may contain mutated tubulin, meaning anti-tubulin drugs can't bind to them in the first place. Or they may contain extra protein pumps that enable cells to quickly eliminate chemotherapy drugs. Anthony Letai, an oncologist at the Dana-Farber Cancer Institute in Boston, says that the importance of the MCL1 pathway in conferring drug resistance probably varies depending on the type of cancer.
"As with any study, you don't know how generalizable it is beyond these cell lines that they study," says Letai. "There's probably plenty of cell lines in which these effects are not observable." The trick, he adds, will be to figure out which cancers follow this model.

Bruce Clurman, an oncologist and molecular biologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, says the findings are exciting and provocative, but preliminary. He notes that FBW7 targets a number of proteins for destruction, not just MCL1. "When you disrupt FBW7, it's hard to know which of these downstream targets are playing what role in the development of cancer." These studies focus on FBW7's role in regulating MCL1, but "it's certainly far from the whole story", he says.
Hayley McDaid, a cancer biologist at Albert Einstein College of Medicine in New York, suggests looking at archived specimens from cancer patients treated with Taxol-like drugs. If Wertz's model holds, the researchers should find a correlation between the presence of FBW7 and response to Taxol. "We need to go in and actually do some sequence analysis on those specimens," she says.

Tumor for Tumor

A new paper appeared in Clinical Cancer Research on fighting tumor with Tumor derived vaccines from dendrite cells. Dendritic cells are critical to the human body's immune system, helping identify targets, or antigens, and then stimulating the immune system to react against those antigens. The new research grew dendritic cells from a sample of a patient's blood, mixed them with proteins from the patient's tumor, and then injected the mixture into the patient as a vaccine. The vaccine then stimulated an anti-tumor response from T-cells, a kind of white blood cell that protects the body from disease.
Abstract:

Purpose: To determine whether an autologous dendritic cell (DC) vaccine could induce antitumor immune responses in patients after resection of colorectal cancer metastases and whether these responses could be enhanced by activating DCs with CD40L.

Experimental Design: Twenty-six patients who had undergone resection of colorectal metastases were treated with intranodal injections of an autologous tumor lysate– and control protein [keyhole limpet hemocyanin (KLH)]–pulsed DC vaccine. Patients were randomized to receive DCs that had been either activated or not activated with CD40L. All patients were followed for a minimum of 5.5 years.

Results: Immunization induced an autologous tumor-specific T-cell proliferative or IFNγ enzyme-linked immunospot response in 15 of 24 assessable patients (63%) and a tumor-specific DTH response in 61%. Patients with evidence of a vaccine-induced, tumor-specific T-cell proliferative or IFNγ response 1 week after vaccination had a markedly better recurrence-free survival (RFS) at 5 years (63% versus 18%, P = 0.037) than nonresponders. In contrast, no association was observed between induction of KLH-specific immune responses and RFS. CD40L maturation induced CD86 and CD83 expression on DCs but had no effect on immune responses or RFS.

Conclusion: Adjuvant treatment of patients after resection of colorectal metastases with an autologous tumor lysate–pulsed, DC vaccine–induced, tumor-specific immune responses in a high proportion of patients. There was an association between induction of tumor-specific immune responses and RFS. Activation of this DC vaccine with CD40L did not lead to increased immune responses. Clin Cancer Res; 16(22); 5548–56. ©2010 AACR.

Citation: Richard J. Barth, Jr., Dawn A. Fisher, Paul K. Wallace, Jacqueline Y. Channon, Randolph J. Noelle, Jiang Gui, and Marc S. Ernstoff, 'A Randomized Trial of Ex vivo CD40L Activation of a Dendritic Cell Vaccine in Colorectal Cancer Patients: Tumor-Specific Immune Responses Are Associated with Improved Survival', Clin Cancer Res November 15, 2010 doi:10.1158/1078-0432.CCR-10-2138

Somatic Mutations in Four Human Cancers

[Source : From mass genomics]
In a letter to Nature this week, a group from Genentech presents an elegant analysis of 2,576 somatic mutations across 441 tumors comprised of breast, lung, ovarian, and prostate cancer types and subtypes. Using something called “mismatch repair detection” (MRD) technology, the authors surveyed 1,507 candidate genes spanning some 4 megabases of sequence, largely comprised of known cancer genes and “druggable” genes. MRD apparently uses E. coli to isolate amplicons that contain mutations relative to a reference sequence, which are then assessed for variations by a resequencing tiling array. Matched normal samples were also screened (in pools of five) to eliminate germline events.

I admit to knowing little about MRD or its capabilities, but I’m very familiar with the validation platform (Sequenom), which has proven its value in the HapMap, Cancer Genome Atlas (TCGA), and 1,000 Genomes projects.
Significantly Mutated Genes

Any doubts I had concerning a study from the private sector were quickly swept away, not just by the quality of the journal, but by the analysis that the authors presented. Simply put, I was enchanted. Figure 1, for example, illustrates the significantly mutated gene (SMG) analysis with a grid of eight bubble plots, one per cancer subtype. Significant genes are notable not just by their position on the Y-axis (Mutation q-score), but the size of the bubble, which corresponds to the number of mutations.

The set of SMGs varied across type and subtype, but some patterns immediately jump out. PIK3CA and TP53 were the most significant across three breast cancer subtypes. TP53, in fact, was significant across all eight subtypes, most strikingly in lung and ovarian cancer. KRAS stood out in pancreatic cancer and lung adenocarcinoma, but not squamous lung carcinoma.

On average across all tumors studied here, the authors found 1.8 protein-altering mutations per megabase, with the highest rates seen in lung adenocarcinomas (3.5/Mb) and squamous carcinomas (3.9/Mb). The lowest mutation rate (0.33/Mb) was in prostate tumors, 75% of which harbored the TMPRSS2-ERG gene fusion. These patterns are consistent with Figure 1, where prostate shows a sparse handful of significant genes, while lung cancers have large and diverse sets of them.
Integrated Copy Number and Mutation Analysis

Next, the authors integrated their mutations with Agilent 244K array CGH copy number data to identify genes that were significantly altered, either by mutation, copy number, or both. In Figure 2a, the authors plotted significantly altered genes by their copy number gain or loss, which nicely separated oncogenes and tumor-suppressor genes. The integrated analysis identified 35 additional cancer genes including STK11, EPHB1, and notably GNAS (the G-protein alpha subunit). GNAS proved an important finding, as it was mutated and amplified across several human cancers.
Pathway-based and Recurrency Analyses

The integrated dataset identified two pathways - RTK signaling and RAS/MAPK as the most significantly altered across all tumor types. Furthermore, when the authors compared their dataset with the COSMIC database and the findings of recent cancer sequencing studies, they pinpointed novel recurrent mutations in several genes including HER2, NOTCH4, and PIK3R1.

The authors conclude that their study “represents a substantial expansion of the knowledge base of cancer somatic mutations,” and I tend to agree. They not only generated a rich dataset, but also analyzed and presented it in comprehensive fashion. Furthermore, they (perhaps unsurprisingly) identify numerous cancer genes that are druggable targets, thereby translating these findings into actionable information.

References

Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K, Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS, Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ, Faham M, & Seshagiri S (2010). Diverse somatic mutation patterns and pathway alterations in human cancers. Nature PMID: 20668451

Environment and cancer

Foundation Medicine: a new genomic approach to cancer diagnosis

[Reposted from Times Online]

Lungcancer

On June 25, 2000, Bill Clinton welcomed Francis Collins and Craig Venter to the White House to announce the completion of the first draft of the human genome. Ten years on, scientists have taken many important steps towards understanding what this sequence means for human health, yet most of the medical benefits still lie in the future. Except, that is, in one important disease. Cancer.

Cancer is at root a disease of the genes, caused when mutations trigger uncontrolled cell division. Understanding the genome is thus a highly valuable weapon against tumours, as a knowledge of the molecular defects that drive them can allow doctors to attack them with targeted therapies. In the past decade, several of these smart drugs have hit the market, often transforming the prognosis for patients.

Imatinib (Glivec or Gleevec), for instance, has turned chronic myeloid leukaemia into a controllable disease. Patients with colon cancer can benefit from cetuximab (Erbitux) only if their tumours do not carry a mutation in a gene called KRAS. Trastuzumab (Herceptin) is often highly effective against breast cancers with a HER2 mutation, while gefitinib (Iressa) and erlotinib (Tarceva) work against lung tumours with an EGFR mutation. And most recently,an experimental drug called PLX4032 has had hugely promising results against melanomas with a particular mutation of the BRAF gene, offering hope for treatment of a cancer with a terrible prognosis.

The move towards such targeted therapies is certain to be a dominant theme of oncology over the next decade. But if they are truly to transform patient care, they need to be accompanied by simple diagnostics -- the tests that identify the genetic subtype of a patient's tumour, so that doctors can choose the appropriate therapy. As Sir John Bell has pointed out, access to such tests is currently patchy, particularly on the NHS.

That is where an exciting new company may soon come in. Foundation Medicine, based in Boston, has today announced it has raised $25 million in funding to develop a one-stop-shop service for genomic diagnosis of cancer. It is going to be a while before it has a product to offer doctors -- its executives are currently engaged in a "listening tour" while they develop their services. But its idea is one that has great potential to help patients to benefit from advances in genomic science.

Foundation is advised by several luminaries in this field, including Eric Lander, director of the Broad Institute, a pioneer of the Human Genome Project, and an adviser to President Obama. Other consultants include Levi Garraway, Matthew Meyerson and Todd Golub, of the Dana Farber Cancer Institute and Harvard Medical School.

Its goal is to broaden significantly the scope of genomic cancer diagnosis, so that samples of each patient's tumours can be analysed not just for one or two genes that might be salient to their treatment, as can happen at present, but for dozens.

A few leading-edge cancer centres, such as Dana Farber and Massachusetts General Hospital (which I visited recently), are starting to do this sort of testing already. Foundation, though, will offer an outsourced service that is suitable for any hospital, to widen access to such diagnosis to patients being treated at ordinary centres that lack the facilities or expertise to do such tests themselves.

Alexis Borisy, Foundation's chief executive, described the idea to me as follows:

"The vision that motivates us at Foundation is that we believe more and more cancer patients are going to benefit from an understanding of the core molecular aberrations that are driving their specific tumours. The technology has moved to a point where it's feasible to decipher those in an individual, patient-specific manner, and to do that in day-to-day oncology practice.

"Our aim is to make that technology available to oncologists, to have an off-the-shelf service for oncologists that they can have complete confidence in."

Dr Meyerson told me:

"Through Foundation Medicine, we’re going to make genomic testing available to all cancer patients. It will, if you like, democratise access to this sort of thing. That is our goal. My hope is we will be doing comprehensive testing on every patient’s cancer."

The notion of testing tumours for multiple mutations is important because of the pace at which scientists are unravelling cancer genomics. It is already emerging that some mutations that are common in one cancer type, such as BRAF in melanoma, also occur at lower frequencies in others -- in this case, in lung cancer. That means that a BRAF inhibitor, though designed for melanoma patients, might also work against lung cancers with the same mutation.

The problem is that while testing lung tumours for EGFR mutations alone makes sense, as that gene is commonly defective in that cancer type, it is not cost-effective to perform the BRAF test in isolation to catch perhaps 1 per cent of patients who might carry it. A reasonably-priced "multiplex text" that covers dozens of genes, however, could be applied to every tumour to provide useful diagnostic clues.

As Borisy put it:

"Some mutations might have been validated in one type of tumour, but could also be relevant and actionable in other settings. In the next couple of years, literally tens of thousands of cancer genomes are going to be analysed. We're going to discover actionable genes that are present in maybe 1 per cent, 0.5 per cent of tumours. At this low frequency, we won't be able to find these by testing one aberration at a time."

Many more rare mutations of this sort are going to emerge as projects like the International Cancer Genome Consortium examine the genomic architecture of cancer over the coming years. Standardized tests that look at dozens, hundreds even, of mutations are going to be necessary if we're to make full clinical use of these insights -- and services like Foundation's are likely to make those accessible.
There's another issue here: gene patenting. As I wrote when a US court last month struck down Myriad Genetics' patent on the breast cancer risk genes BRCA1 and BRCA2, broad patent rights over genes have the power to severely restrict multiplex testing of the type Foundation intends to offer. It just isn't practical to pay royalties to dozens of different patent holders over dozens of different mutations for which you might test.

Posted by Mark Henderson on April 15, 2010 in Cancer , Genetics |

A quick checklist for cancer prevention

An article appeared in Self October 2008 issue. Here is the excerpt:

Slash your cancer risk in minutes a day
Little lifestyle changes can lower your odds of hearing the dreaded diagnosis. Slip them into your routine and sleep better tonight.
By Aviva Patz
From the October 2008 Issue

Slash your cancer risk in minutes a day
More from this package


Stay weight wise

Excess pounds boost cancer risk, a study in The Lancet shows. Build an exercise habit now to head off trouble: The American Cancer Society (ACS) recommends aiming for 30 minutes of activity five days a week. When you hit your 45th birthday, make sure you're also doing 45 minutes of strength training twice weekly to minimize metabolic slowdown. "Beginning in our mid-40s, we lose up to a third of a pound of muscle a year and gain it back as fat, and fat burns fewer calories than muscle," says Miriam Nelson, Ph.D., director of Tufts University John Hancock Center for Physical Activity and Nutrition in Boston.


Practice peace

Say ahhh! High levels of the stress hormone cortisol may inhibit a key gene from suppressing tumor growth, findings in the journal Genes, Chromosomes & Cancer suggest. Tame tension with this formula from the University of Pittsburgh Medical Center Healthy Lifestyle Program: 1. Take deep belly breaths. You slow and elongate brain waves, bringing on calm. 2. Watch your favorite comedy. Enjoying a good laugh activates the areas of the brain that govern humor, in turn suppressing the brain's stress regions. 3. Adopt an uplifting mantra. Try "I love my life!" and repeat it when you're happy. You will train your mind to associate the phrase with being content. Then when you're on edge, chant your mantra and you'll immediately feel at ease.

Bake, don't burn

Grilling beef, poultry and fish until it's charred to a crisp can turn amino acids and other substances in the meat into heterocyclic amines (HCAs), compounds that have been linked to cancer. "HCAs are 10 times more potent than most other environmental carcinogens," says Kenneth Turteltaub, Ph.D., a toxicologist at Lawrence Livermore National Laboratory in California. Try these cookin'-good tips!
Marinate meat before grilling. Soaking chicken breasts in a mixture of cider vinegar, olive oil, lemon juice and spices reduced HCA formation by 92 to 99 percent, notes a study published in Food and Chemical Toxicology. "Marinating creates a barrier between the hot surface and meat, enough to lower the temperature and prevent HCAs from forming," Turteltaub says.
Keep the grill temp below 325 degrees, the point at which HCAs begin to form.
Grill meat or fish in punctured aluminum foil to protect against flare-ups. When fat drips on the hot coals, it forms HCAs, plus other carcinogens called polycyclic aromatic hydrocarbons that rise with the smoke.
Microwave beef burgers for one to three minutes before browning; doing so reduces HCA production by 95 percent, according to a study in Food and Chemical Toxicology. Prior to grilling, discard the juices, which contain the building blocks of HCAs.
Flip burgers often—about once a minute. This action keeps meat juices from getting too hot and activating HCA formation.

Personalized cancer treatment

Here is the link

Cancer Alternative Medicine(CAM)

I have subscribed to one mailing list, that is cancercaregiversareus is a yahoo mailing group. While reading the list I suddenly had this urge to write this article.

In the mailing group there are real people with real experience with life and cancer. Most people suffer uncannily from the cancer treatment alone. Be that chemotherapy, radiation, monoclonal antibody therapy or anything modern medicine can offer. Some of them incapacitates people for the rest of their lives and the quality of life is suddenly snatched away from them. I was wondering can we not try an alternative approach than going straight to our oncologists who have no idea about nutrition and healthy life style? I have read most of the stories where the doctors prescribe people to have some energy drinks that are available in stores. They have no clue that those drinks are full of preservatives, sugar and other unwanted stuff..

There are numerous examples where people have cured their own cancer by sheer will to survive and taking their treatment to their own hands. One such example is in Oprah show where Randy Pausch and an aspiring model Kris were featured together - both had cancer[ A link here]. Where she is stable with her vegetable juices, Randy passed away with all the great treatments he received. The point I am trying to make here is to create some kind of awareness among people to eat right, change life style to keep cancer at bay. Even those that are not having cancer need to adopt a healthy life style that will give them immunity from cancer.

Here are a few points I would like to suggest people with or without cancer:

1. Avoid Sugar completely.Cancer is known to feed on sugar.
2. Avoid trans fat - instead eat good fat(uncooked olive oil, flax seed oil, pumpkin seed, sunflower seed etc.)
3. If you can grow wheat grass and barley grass at home. Consume at least 1 ounce juice every morning.
4. Eat raw or half cooked vegetable that are highly pigmented.
5. Do regular exercise - atleast 5 times a week for at least 30 minutes.
6. Do yoga to relieve stress - atleast 3 times a week.
7. Try sweating everyday.
8. Try avoiding meat in all forms if possible stop eating dairy and wheat.
9. Drink plenty of water.
10. Avoid drinking, smoking.
11. If you can buy Essiac tea. They are very good for your immunity.
12. Avoid caffeine.
13. NO canned food, No packed food.
14. Resort to freshly cooked meal. Don't have those energy drinks, or drinks that are readily available in stores.
15. Stop eating outside: The food cooked outside have the least food value.
16. STOP SODA ALTOGETHER.
17. NO ICE CREAMS.
18. Try eating 3-4 colorful fruits a day.
19. Eat wild rice and vegetables regularly.
20. Meditate if you can.

These are surely going to reduce your cancer risks as well as help you get rid of your cancer if you already have it.

I was very happy to know that NIH is now funding CAM(Cancer alternative medicine)

Here is the announcement:

NEW COMPLEMENTARY AND ALTERNATIVE MEDICINE RESEARCH CENTERS TARGET
STRESS-RELATED ILLNESSES, OBESITY, CANCER, AND OTHER CONDITIONS

The National Institutes of Health's National Center for Complementary
and Alternative Medicine (NCCAM) has added four new Centers of
Excellence for Research on Complementary and Alternative Medicine
(CERCs) to its research centers program. The new centers will add to
knowledge about complementary and alternative medicine (CAM) approaches
and their potential in treating and preventing diseases and conditions
that are common among Americans.

In NCCAM's CERC program, highly accomplished researchers across a
variety of disciplines apply cutting-edge technology to projects in CAM.
The new centers and their projects are as follows.

WISCONSIN CENTER FOR THE NEUROSCIENCE AND PSYCHOPHYSIOLOGY OF MEDITATION
Principal Investigator: Richard J. Davidson, Ph.D.
Institution: University of Wisconsin, Madison
Dr. Davidson's team will examine the impact of two forms of meditation
-- loving-kindness/compassion meditation and mindfulness meditation --
on the brain and body, focusing on the regulation of emotion and on
emotional reactivity. Potential applications in health include
biological and behavioral processes linked with emotions and/or stress,
such as recurrent depression.

METABOLIC AND IMMUNOLOGIC EFFECTS OF MEDITATION
Principal Investigator: Frederick M. Hecht, M.D.
Institution: University of California, San Francisco
Dr. Hecht and his colleagues will study a program combining mindfulness
meditation, mindful eating (the practice of awareness and attentiveness
in the present moment while eating), and a diet and exercise program,
for use in obesity and metabolic syndrome. They will test whether this
program helps alter participants' hormonal responses to stress and helps
enhance and maintain weight loss. Metabolic syndrome involves a cluster
of abnormalities--including increased cholesterol, high blood pressure,
and insulin resistance--that increases one's risk for developing
diabetes and cardiovascular diseases.

CAM AS COUNTERMEASURES AGAINST INFECTIOUS AND INFLAMMATORY DISEASE
Principal Investigator: Mark A. Jutila, Ph.D.
Institution: Montana State University, Bozeman
This center will study biologically based CAM therapies and their
effects on immune system function in infectious and inflammatory
diseases. One project focuses on effects of botanical extracts--from
apple polyphenols, which are concentrated in apple skins, and from
yamoa, which comes from the bark of an African gum tree -- on white
blood cells, using models of infection and inflammation of the
intestinal mucosa. A second project examines two compounds in licorice
root -- glycyrrhizin and 18-glyrrhetinic acid--for their potential
antiviral effects in models of influenza and stomach virus. A third
project will focus on bacterial products to see how they treat
autoimmune diseases, like arthritis, which may also help build
understanding of probiotics' action.

CENTER FOR HERBAL RESEARCH ON COLORECTAL CANCER
Principal Investigator: Chun-Su Yuan, M.D., Ph.D.
Institution: University of Chicago
Colorectal cancer is the third most common cancer and the third leading
cause of cancer-related death. Dr. Yuan and his colleagues will examine
the anti-tumor effects of different preparations of the herbs American
ginseng (Panax quinquefolius) and notoginseng (Panax notoginseng). They
will seek to learn more, through laboratory and animal studies, about
how these herbs act upon cellular and molecular pathways of the
mechanisms of cancer inhibition.

"The new CERCs, all based on strong preliminary work, apply
natural-product and mind-body CAM approaches across a range of health
conditions that affect the American public," said Josephine P. Briggs,
M.D., NCCAM director. "Their multidisciplinary, collaborative structure
increases opportunities for improving health and discovering insights
into important aspects of human biology."

The grants provide five years of support and bring the total number of
CERCs to 11. To learn more about NCCAM's research centers, go to
.

The National Center for Complementary and Alternative Medicine's mission
is to explore complementary and alternative medical practices in the
context of rigorous science, train CAM researchers, and disseminate
authoritative information to the public and professionals. For
additional information, call NCCAM's Clearinghouse toll free at
1-888-644-6226, or visit the NCCAM Web site at .

The National Institutes of Health (NIH) -- The Nation's Medical Research
Agency -- includes 27 Institutes and Centers and is a component of the
U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational
medical research, and it investigates the causes, treatments, and cures
for both common and rare diseases. For more information about NIH and
its programs, visit .

CONTACT: NCCAM Press Office, 301-496-7790

Give your immune system a chance..

I wrote this article for an annual newsletter for a small community of non-scientists. I thought it will be useful to post it on my blog as well. Here is the article.

Give your immune system a chance

If we don’t use a particular instrument for sometime, then it gathers junk. If we don’t use our brain often, then brain cells degenerate. Similarly, if we don’t use our immune system for sometime, then immune system starts corroding. What an amazing fact it is!! Yes, this is true… It is said that “If you take medicine, then cold goes away in just a week and if you don’t, then cold gets away in 7 long days”. The reason I chose to write this article is to introduce our amazing immune system in over simplified terms that we have little or no knowledge about.
Humans are highly evolved organisms belonging to class vertebrata that have a very well defined vertebral column. Almost all life forms have immune system. But this immune system has continuously improved to reach its highest state in jawed vertebrates. Humans are the highest life forms having the most sophisticated immune system. During evolution, immune system has been continuously undergoing modifications to help us fight elimination by natural selection.

Our Immune System:

Our immune system is broadly classified into two groups;
1. Innate immunity 2. Acquired immunity.
Innate Immunity is what we are born with and acquired immunity is what we acquire during our life time against certain types of response. The response could be infection, toxins, our own cells gone bad etc. Innate immunity comes to play as an immediate response to a threat to our body from an external agent – be it bacteria, virus, toxins, proteins etc. When innate immunity realizes that its resources are not adequate enough to fight against the disease causing agent, it passes the responsibility to the more sophisticated acquired immunity. Acquired immunity uses all its inbuilt tricks to fight against the attacker until it wins. Once the battle is won by the acquired immune system, the cells remember that. So, in future if there is an attack from a similar organism then the immune system reacts immediately, effortlessly. That is why we acquire life long immunity against a particular type of disease we already had.
Typically our immune system comprises of fighter cells and fighter molecules. The fighter cells are often known as B cells(Produced by Bone marrow) or T cells(Produced by Thymus) and the fighter molecules or antibodies are produced by these fighter cells. The fighter T cells often roam around within our system through our vascular system (blood/lymph network ) and clean it up when they see any foreign particle floating around. They do this by phagocytosis(Phago -> to eat; cytosis -> cellular process [Fig 1] ). It is interesting how they recognize the foreign elements. They generally have an antenna type of molecule on the top of their cell membranes that act as a sensor. The B cells are the factories that produce the sensor molecules. Through out our life time, our immune system builds its memory to identify good and bad elements. This system is highly efficient in humans and it not only eliminates our attackers but also cleans our own dead cells, cancerous cells and any other cell that has gone wrong by a process called as apoptosis. Typically if there is a new attack on our body, generally the memory forming cells try to look at its existing database and determine if the response is already preserved in cellular memory. If it finds out that it is not listed, then it goes back to its expression system, where it creates new fighter molecules that will be a fitting reply to the attacker.
Genetics of Immunity:
The attackers to our system produce a molecule (usually a protein) called ‘antigen’ and our body’s antidote for that is ‘antibody’. Often antibody binds and incapacitates the antigen and makes it inactive[Fig – 2]. Antibodies are highly specific and can identify millions of different antigens – in other words we are capable of producing millions of specific antibodies. As per the famous one gene one enzyme hypothesis (Beadle and Tatum's 1941 Breakthrough), we should have several million of genes to produce several million of antibodies, but we have in total only 30,000 or so genes in our body, and our immune related genes are not even more than a thousand.In that case how we are capable of producing millions of proteins from just thousand genes?
Structurally antibodies are comprised of 4 polypeptide(=proteins) - 2 heavy chains and 2 light chains. Each of these 4 polypeptides have a variable region and a constant region[fig-3]. The constant region forms the structural unit of the antibody while the variable region forms the functional unit. The variable parts are the ones that make the antibody so specific. Often the variable parts are the products of alternative splicing. So, now what is this ‘alternative splicing’? In order to understand the splicing event, we need to know little bit about the structure of our genes. Our genes have coding(useful) and non-coding(not so useful) regions. The coding parts are called as exons and the non-coding parts are called as introns. In a typical human gene, the exons and introns alternate with each other. Before a gene is expressed all the exons are joined together, that is translated to form a valid protein. In alternative splicing event all the exons don’t join together in the same order or same number. They join in different permutations and combinations. For instance if a gene has 4 exons, then it may join them to form > 4 products[Fig – 4].Here, we can’t speak strictly in mathematical terms because there are a certain sets of rules in splicing, that makes the straight forward calculation very complicated. This procedure of creating a specific product against a antigen can be compared to finding a drug target for a particular disease – only it takes place at a cellular level and it happens very quickly! The moment it finds the molecule that can fight against the attacker, it remembers that and starts producing them at a very higher number. The war takes place and generates heat. That is why often we develop fever against a certain infection. Once the fight is over, the product is remembered in our cellular memory. So, when there is another attack by same organism, we already have immunity against it. This is the same principle how the vaccination works. Vaccines are often the dead bacteria or viruses that cause a disease. Once injected into the body it elicits the immune response and it stays there for the entire life time. So, the individual gets immunity against that disease for the whole life.
Sometimes, the immune system can’t fight that well especially when our immune system is week or under utilized, it generally looses the disease fighting abilities. So, it is essential in that case to have medical intervention. In order to remain healthy we need to exercise our immune system as well and strengthen it.
Immune boosters:
Healthy habits are great immune boosters. The best food for healthy immune system is colorful fruits and vegetables. Apart from food, regular exercise, adequate sleep, drinking enough clean water, vitamins(mostly from natural plant sources – they get absorbed well), reducing stress helps improve our compromised immune system. So, the bottom line here is to increase our cellular memory so that it is capable of identifying a myriad of infectious particles and fight against it without much trouble.
Certain food are know to weaken our immune system are coffee, sugar, soda, alcohol, preserved food(mostly canned food). So to conclude: stay healthy, eat healthy and do regular exercise to minimize doctor visits.

Fig – 1: Phagocytosis


Fig – 2 : Antigen – Antibody binding


Fig – 3 : Structure of a immunoglobulin

Fig – 4 : Gene Structure and alternative splicing

BMC cancer journals

BMC has a special cancer issue. The link is here

Once you get to the site, you will see a large number of other cancer related journals on the menu bar. They are all free!!

BMC Cancer
BMC Medical Genomics
Breast Cancer Research
Cancer Cell International
Current Oncology Reports
Current Treatment Options in Oncology
Genome Medicine
Head & Neck Oncology
Infectious Agents and Cancer
International Seminars in Surgical Oncology
Journal of Biology
Journal of Carcinogenesis
Journal of Experimental & Clinical Cancer Research
Journal of Hematology & Oncology
Molecular Cancer
Radiation Oncology
UroOncology
World Journal of Surgical Oncology

Cancer alternative treatment

This has been my favorite topic for the last 3 years. Having said that does not mean I completely shun traditional treatment. I strongly believe there is always a non-invasive alternative way to deal with this. I have been looking for research as well as other articles published online on this subject and collected quite a few.

The other day I happened to see Oprah's page on "confronting death". Following is the uplifting excerpt of the show:

In 2003, Kris was a model and aspiring actress. Then she received devastating news—she had a rare form of cancer that was in its most serious stage. Kris immediately set to figuring out what to do about the cancer…and picked up a camera to record the process.

After getting prescribed drastic treatments—including a recommendation for a triple organ transplant—Kris searched for other opinions and explored alternative options like health food and yoga. Her journey was made into the documentary Crazy Sexy Cancer, which aired on TLC, and the book Crazy Sexy Cancer Tips. "A lot of people look at me like I have 10 heads when I say it, but cancer's been my guru, it's my teacher," Kris says in the film. "It teaches me every day the hard things and the beautiful things."

Years later, Kris says the tumors on her liver and lungs are completely stable. "I'm happy and, I think, healthier than I was before I was diagnosed," she says.

In her kitchen, Kris whipped up a special health cocktail for Dr. Oz using cucumber, celery, sprouts and kale. "It's green," she says. "Whatever is in the refrigerator that's green, it's in my juice."

"And it tastes good," Dr. Oz says.

Kris says this healthy lifestyle is far removed from her old self. "I did martinis before, now I do green drinks," she says. "I knew when I was diagnosed with cancer the only thing I could control was what I ate, what I drank and what I would think. I thought the best place to start was with what I put in my mouth. It's one of the many reasons I think I feel better."

The biggest change Kris says she made in her fight with cancer was in her mind. "I think that life is just too sweet to be bitter," she says. "Once I was able to change my focus, desperation led to inspiration. Once I was able to do that, I looked around me. I made so many changes and I thought, 'This is an awesome life. I mean, honestly, I don't think anybody has a better life than me.'"

Instead of focusing on cancer and death, Kris says she focuses on staying in the moment of living. "How do you live your life with the knowledge of cancer?" she says "I might not ever be able to get rid of it, but I can't let that ruin my life."
link here

Growing wheat grass

Recently I have become a wheat grass freak. After hearing the uncountable number of benefits the freshly squeezed juice has, I have taken up this hubby of growing these on my trays. Initially I was following all the protocols published in the internet, but later it proved to be kind of difficult to follow with the involvement of soil, insects etc. Not to mention the dirt. So, I toyed with the idea of growing them soil less. Wheat like many other seeds have storage products that breaks down during germination of seeds to provide necessary nutrients for the seeds to sprout and grow till they start photosynthesizing. I was also looking for the wheat grass kits that are available that does not need soil. To my surprise, they were so much over priced!! I am hoping these tips will be beneficial for those who don't own a large backyard - yet want to be able to produce decent amount of grass for daily consumption.

Ingredients:

5 shallow trays of the dimension of 2 ft tall X 1 ft wide. If that is not available, then have smaller trays that are available in any garden store. If they have no holes, just poke holes in them, so that water gets drained easily.[Fig - 1]
Spread kitchen paper or any other thicker blotting paper on the tray. Soak around 1/2 cup of wheat seeds for about 24 hours(till you see the germ tubes). Spread the pre-soaked wheat seeds on the paper evenly[Fig - 2]. Put another layer of kitchen paper on the top of the seeds without exposing any area to light[Fig - 4]. Now moisten the papers and let them drain thoroughly. Always try to keep the paper wet. In another 48 hours you will notice the upper layer of paper has been lifted a nit. this is an indication that the wheat seeds have germinated and the fine root hair is adding to the volume. After about 3-4 of sowing you can see the epicotyls(the part of the seedling upper to the root looks green. At that point you can take off the upper paper. Again continue spraying water 2-3 times a day. In about 10 days you will have wheat grass about 3-4 inch in length ready for harvest[fig - 5]. You can either juice with a manual juicer or a mixie[Fig - 6].

Essence of wheat grass

I have been drawn to wheat grass after reading a number of articles that are going round in internet. To find the validity, I looked for the original wheat grass article on wikipedia. The first research on wheat grass dates back to 1930s when an agricultural chemist Charles F. Schnabel fed his sick poultry stock with dried wheat grass. He found not only the poultry revived but also they produced more good quality eggs than the control group. In rural India, the infertile cows are left in wheat field to restore their fertility. Although the claim that 1 oz of wheat grass juice has enough nutrients as 1 KG of vegetable does not sound right. I just saw some data and it may be as good as 1 oz of broccoli, spinach, carrot and some other vegetables together. Still exciting... When we eat vegetables in different forms we have almost lost a lots of nutritional values altogether. Another great thing I read about wheat grass is the readiness with which the componenets are absorbed by our system. That may make it a superfood.

Although specific research on this is lacking, I would not doubt the beneficial effects of wheat grass for the fact that "there are many well known facts that are yet to be proved by scientific research". For this I looked at pubmed and selected the limit as 'alternative medicine' + wheat grass. There was a total of 331 articles showed up as of today and here are just a few of research articles I pulled out.

1) Wheat grass juice reduces transfusion requirement in patients with thalassemia major: a pilot study

2) Wheat grass juice may improve hematological toxicity related to chemotherapy in breast cancer patients: a pilot study

3) Wheat grass juice appeared effective and safe as a single or adjuvant treatment of active distal UC.

4)Adjuvant fermented wheat germ extract (Avemar) nutraceutical improves survival of high-risk skin melanoma patients: a randomized, pilot, phase II clinical study with a 7-year follow-up

5)Avemar, a nontoxic fermented wheat germ extract, induces apoptosis and inhibits ribonucleotide reductase in human HL-60 promyelocytic leukemia cells.

6) The formulation of WIT-NP, in which WGA(wheat germ aglutinins) is conjugated to the surface of paclitaxel and IPM-loaded PLGA nanoparticles, significantly potentiates the anticancer activity of paclitaxel

7) Fermented wheat germ extract (Avemar) in the treatment of cancer and autoimmune diseases: Avemar, the product of industrial fermentation of wheat germ, possesses unique cancer-fighting characteristics. Taken orally, Avemar can inhibit metastatic tumor dissemination and proliferation during and after chemotherapy, surgery, or radiation. Benefits of Avemar treatment have been shown in various human cancers, in cultures of in vitro grown cancer cells, in the prevention of chemical carcinogenesis, and also in some autoimmune conditions. This document reviews the clinical and experimental results obtained with this extract so far. Special references are made for its safety, including its coadministration with anticancer drugs, as well as for its immunomodulatory activity, its molecular targets, and its use in cancer clinical trials.

The list goes on and on. So, the properties of wheat grass is definitely something that needs further attention. The studies have been done with respect to wheat grass and auto immune disorders, ulcerative colitis, cancer etc. I think this can further be expanded to studies on endometriosis, female, male fertility, anti aging, diabetes and so on and so forth.

There are often mention of macronutrients in wheat grass, but there are lots of micronutrients that need be studied in great detail. A study need to be conducted to profile the nutritional property of this wonder grass vs other formulated vitamins.

Cancer's Sweet Tooth

I am a firm believer of natural healing and I strongly believe that systemic diseases like cancer develop over a period of time. When the body is no longer able to fight malignant cells that are produced on a day to day basis, the malignant cells win and almost take over our body. That is why in younger people where the immune system is strong, cancer growth are rare. Recently, I came across this very well written article about the relationship between cancer and Sugar. Although this is a very well established fact, very few doctors seem to be aware of it. The health drinks often they prescribe to patients is so full of sugar. Here is the summary of this article:

by Patrick Quillin, PHD, RD, CNS
From The April 2000 Issue of Nutrition Science News

During the last 10 years I have worked with more than 500 cancer patients as director of nutrition for Cancer Treatment Centers of America in Tulsa, Okla. It puzzles me why the simple concept "sugar feeds cancer" can be so dramatically overlooked as part of a comprehensive cancer treatment plan.

Of the 4 million cancer patients being treated in America today, hardly any are offered any scientifically guided nutrition therapy beyond being told to "just eat good foods." Most patients I work with arrive with a complete lack of nutritional advice. I believe many cancer patients would have a major improvement in their outcome if they controlled the supply of cancer's preferred fuel, glucose. By slowing the cancer's growth, patients allow their immune systems and medical debulking therapies -- chemotherapy, radiation and surgery to reduce the bulk of the tumor mass -- to catch up to the disease. Controlling one's blood-glucose levels through diet, supplements, exercise, meditation and prescription drugs when necessary can be one of the most crucial components to a cancer recovery program. The sound bite -- sugar feeds cancer -- is simple. The explanation is a little more complex.

The 1931 Nobel laureate in medicine, German Otto Warburg, Ph.D., first discovered that cancer cells have a fundamentally different energy metabolism compared to healthy cells. The crux of his Nobel thesis was that malignant tumors frequently exhibit an increase in anaerobic glycolysis -- a process whereby glucose is used as a fuel by cancer cells with lactic acid as an anaerobic byproduct -- compared to normal tissues.1 The large amount of lactic acid produced by this fermentation of glucose from cancer cells is then transported to the liver. This conversion of glucose to lactate generates a lower, more acidic pH in cancerous tissues as well as overall physical fatigue from lactic acid buildup.2,3 Thus, larger tumors tend to exhibit a more acidic pH.4

This inefficient pathway for energy metabolism yields only 2 moles of adenosine triphosphate (ATP) energy per mole of glucose, compared to 38 moles of ATP in the complete aerobic oxidation of glucose. By extracting only about 5 percent (2 vs. 38 moles of ATP) of the available energy in the food supply and the body's calorie stores, the cancer is "wasting" energy, and the patient becomes tired and undernourished. This vicious cycle increases body wasting.5 It is one reason why 40 percent of cancer patients die from malnutrition, or cachexia.6

Hence, cancer therapies should encompass regulating blood-glucose levels via diet, supplements, non-oral solutions for cachectic patients who lose their appetite, medication, exercise, gradual weight loss and stress reduction. Professional guidance and patient self-discipline are crucial at this point in the cancer process. The quest is not to eliminate sugars or carbohydrates from the diet but rather to control blood glucose within a narrow range to help starve the cancer and bolster immune function.

The glycemic index is a measure of how a given food affects blood-glucose levels, with each food assigned a numbered rating. The lower the rating, the slower the digestion and absorption process, which provides a healthier, more gradual infusion of sugars into the bloodstream. Conversely, a high rating means blood-glucose levels are increased quickly, which stimulates the pancreas to secrete insulin to drop blood-sugar levels. This rapid fluctuation of blood-sugar levels is unhealthy because of the stress it places on the body (see glycemic index chart, p. 166).


Sugar in the Body and Diet
Sugar is a generic term used to identify simple carbohydrates, which includes monosaccharides such as fructose, glucose and galactose; and disaccharides such as maltose and sucrose (white table sugar). Think of these sugars as different-shaped bricks in a wall. When fructose is the primary monosaccharide brick in the wall, the glycemic index registers as healthier, since this simple sugar is slowly absorbed in the gut, then converted to glucose in the liver. This makes for "time-release foods," which offer a more gradual rise and fall in blood-glucose levels. If glucose is the primary monosaccharide brick in the wall, the glycemic index will be higher and less healthy for the individual. As the brick wall is torn apart in digestion, the glucose is pumped across the intestinal wall directly into the bloodstream, rapidly raising blood-glucose levels. In other words, there is a "window of efficacy" for glucose in the blood: levels too low make one feel lethargic and can create clinical hypoglycemia; levels too high start creating the rippling effect of diabetic health problems.

The 1997 American Diabetes Association blood-glucose standards consider 126 mg glucose/dL blood or greater to be diabetic; 126 mg/dL is impaired glucose tolerance and less than 110 mg/dL is considered normal. Meanwhile, the Paleolithic diet of our ancestors, which consisted of lean meats, vegetables and small amounts of whole grains, nuts, seeds and fruits, is estimated to have generated blood glucose levels between 60 and 90 mg/dL.7 Obviously, today's high-sugar diets are having unhealthy effects as far as blood-sugar is concerned. Excess blood glucose may initiate yeast overgrowth, blood vessel deterioration, heart disease and other health conditions.8

Understanding and using the glycemic index is an important aspect of diet modification for cancer patients. However, there is also evidence that sugars may feed cancer more efficiently than starches (comprised of long chains of simple sugars), making the index slightly misleading. A study of rats fed diets with equal calories from sugars and starches, for example, found the animals on the high-sugar diet developed more cases of breast cancer.9 The glycemic index is a useful tool in guiding the cancer patient toward a healthier diet, but it is not infallible. By using the glycemic index alone, one could be led to thinking a cup of white sugar is healthier than a baked potato. This is because the glycemic index rating of a sugary food may be lower than that of a starchy food. To be safe, I recommend less fruit, more vegetables, and little to no refined sugars in the diet of cancer patients.


What the Literature Says
A mouse model of human breast cancer demonstrated that tumors are sensitive to blood-glucose levels. Sixty-eight mice were injected with an aggressive strain of breast cancer, then fed diets to induce either high blood-sugar (hyperglycemia), normoglycemia or low blood-sugar (hypoglycemia). There was a dose-dependent response in which the lower the blood glucose, the greater the survival rate. After 70 days, 8 of 24 hyperglycemic mice survived compared to 16 of 24 normoglycemic and 19 of 20 hypoglycemic.10 This suggests that regulating sugar intake is key to slowing breast tumor growth (see chart, p. 164).

In a human study, 10 healthy people were assessed for fasting blood-glucose levels and the phagocytic index of neutrophils, which measures immune-cell ability to envelop and destroy invaders such as cancer. Eating 100 g carbohydrates from glucose, sucrose, honey and orange juice all significantly decreased the capacity of neutrophils to engulf bacteria. Starch did not have this effect.11

A four-year study at the National Institute of Public Health and Environmental Protection in the Netherlands compared 111 biliary tract cancer patients with 480 controls. Cancer risk associated with the intake of sugars, independent of other energy sources, more than doubled for the cancer patients.12 Furthermore, an epidemiological study in 21 modern countries that keep track of morbidity and mortality (Europe, North America, Japan and others) revealed that sugar intake is a strong risk factor that contributes to higher breast cancer rates, particularly in older women.13

Limiting sugar consumption may not be the only line of defense. In fact, an interesting botanical extract from the avocado plant (Persea americana) is showing promise as a new cancer adjunct. When a purified avocado extract called mannoheptulose was added to a number of tumor cell lines tested in vitro by researchers in the Department of Biochemistry at Oxford University in Britain, they found it inhibited tumor cell glucose uptake by 25 to 75 percent, and it inhibited the enzyme glucokinase responsible for glycolysis. It also inhibited the growth rate of the cultured tumor cell lines. The same researchers gave lab animals a 1.7 mg/g body weight dose of mannoheptulose for five days; it reduced tumors by 65 to 79 percent.14 Based on these studies, there is good reason to believe that avocado extract could help cancer patients by limiting glucose to the tumor cells.

Since cancer cells derive most of their energy from anaerobic glycolysis, Joseph Gold, M.D., director of the Syracuse (N.Y.) Cancer Research Institute and former U.S. Air Force research physician, surmised that a chemical called hydrazine sulfate, used in rocket fuel, could inhibit the excessive gluconeogenesis (making sugar from amino acids) that occurs in cachectic cancer patients. Gold's work demonstrated hydrazine sulfate's ability to slow and reverse cachexia in advanced cancer patients. A placebo-controlled trial followed 101 cancer patients taking either 6 mg hydrazine sulfate three times/day or placebo. After one month, 83 percent of hydrazine sulfate patients increased their weight, compared to 53 percent on placebo.15 A similar study by the same principal researchers, partly funded by the National Cancer Institute in Bethesda, Md., followed 65 patients. Those who took hydrazine sulfate and were in good physical condition before the study began lived an average of 17 weeks longer.16

In 1990, I called the major cancer hospitals in the country looking for some information on the crucial role of total parenteral nutrition (TPN) in cancer patients. Some 40 percent of cancer patients die from cachexia.5 Yet many starving cancer patients are offered either no nutritional support or the standard TPN solution developed for intensive care units. The solution provides 70 percent of the calories going into the bloodstream in the form of glucose. All too often, I believe, these high-glucose solutions for cachectic cancer patients do not help as much as would TPN solutions with lower levels of glucose and higher levels of amino acids and lipids. These solutions would allow the patient to build strength and would not feed the tumor.17

The medical establishment may be missing the connection between sugar and its role in tumorigenesis. Consider the million-dollar positive emission tomography device, or PET scan, regarded as one of the ultimate cancer-detection tools. PET scans use radioactively labeled glucose to detect sugar-hungry tumor cells. PET scans are used to plot the progress of cancer patients and to assess whether present protocols are effective.18

In Europe, the "sugar feeds cancer" concept is so well accepted that oncologists, or cancer doctors, use the Systemic Cancer Multistep Therapy (SCMT) protocol. Conceived by Manfred von Ardenne in Germany in 1965, SCMT entails injecting patients with glucose to increase blood-glucose concentrations. This lowers pH values in cancer tissues via lactic acid formation. In turn, this intensifies the thermal sensitivity of the malignant tumors and also induces rapid growth of the cancer. Patients are then given whole-body hyperthermia (42 C core temperature) to further stress the cancer cells, followed by chemotherapy or radiation.19 SCMT was tested on 103 patients with metastasized cancer or recurrent primary tumors in a clinical phase-I study at the Von Ardenne Institute of Applied Medical Research in Dresden, Germany. Five-year survival rates in SCMT-treated patients increased by 25 to 50 percent, and the complete rate of tumor regression increased by 30 to 50 percent.20 The protocol induces rapid growth of the cancer, then treats the tumor with toxic therapies for a dramatic improvement in outcome.

The irrefutable role of glucose in the growth and metastasis of cancer cells can enhance many therapies. Some of these include diets designed with the glycemic index in mind to regulate increases in blood glucose, hence selectively starving the cancer cells; low-glucose TPN solutions; avocado extract to inhibit glucose uptake in cancer cells; hydrazine sulfate to inhibit gluconeogenesis in cancer cells; and SCMT.

A female patient in her 50s, with lung cancer, came to our clinic, having been given a death sentence by her Florida oncologist. She was cooperative and understood the connection between nutrition and cancer. She changed her diet considerably, leaving out 90 percent of the sugar she used to eat. She found that wheat bread and oat cereal now had their own wild sweetness, even without added sugar. With appropriately restrained medical therapy -- including high-dose radiation targeted to tumor sites and fractionated chemotherapy, a technique that distributes the normal one large weekly chemo dose into a 60-hour infusion lasting days -- a good attitude and an optimal nutrition program, she beat her terminal lung cancer. I saw her the other day, five years later and still disease-free, probably looking better than the doctor who told her there was no hope.

Patrick Quillin, Ph.D., R.D., C.N.S., is director of nutrition for Cancer Treatment Centers of America in Tulsa, Okla., and author of Beating Cancer With Nutrition (Nutrition Times Press, 1998).


References

1. Warburg O. On the origin of cancer cells. Science 1956 Feb;123:309-14.

2. Volk T, et al. pH in human tumor xenografts: effect of intravenous administration of glucose. Br J Cancer 1993 Sep;68(3):492-500.

3.Digirolamo M. Diet and cancer: markers, prevention and treatment. New York: Plenum Press; 1994. p 203.

4. Leeper DB, et al. Effect of i.v. glucose versus combined i.v. plus oral glucose on human tumor extracellular pH for potential sensitization to thermoradiotherapy. Int J Hyperthermia 1998 May-Jun;14(3):257-69.

5. Rossi-Fanelli F, et al. Abnormal substrate metabolism and nutritional strategies in cancer management. JPEN J Parenter Enteral Nutr 1991 Nov-Dec;15(6):680-3.

6. Grant JP. Proper use and recognized role of TPN in the cancer patient. Nutrition 1990 Jul-Aug;6(4 Suppl):6S-7S, 10S.

7. Brand-Miller J, et al. The glucose revolution. Newport (RI) Marlowe and Co.; 1999.

8. Mooradian AD, et al. Glucotoxicity: potential mechanisms. Clin Geriatr Med 1999 May;15(2):255.

9. Hoehn, SK, et al. Complex versus simple carbohydrates and mammary tumors in mice. Nutr Cancer 1979;1(3):27.

10. Santisteban GA, et al. Glycemic modulation of tumor tolerance in a mouse model of breast cancer. Biochem Biophys Res Commun 1985 Nov 15;132(3):1174-9.

11. Sanchez A, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr 1973 Nov;26(11):1180-4.

12. Moerman CJ, et al. Dietary sugar intake in the aetiology of biliary tract cancer. Int J Epidemiol 1993 Apr;22(2):207-14.

13. Seeley S. Diet and breast cancer: the possible connection with sugar consumption. Med Hypotheses 1983 Jul;11(3):319-27.

14. Board M, et al. High Km glucose-phosphorylating (glucokinase) activities in a range of tumor cell lines and inhibition of rates of tumor growth by the specific enzyme inhibitor mannoheptulose. Cancer Res 1995 Aug 1;55(15):3278-85.

15. Chlebowski RT, et al. Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled clinical experience. Cancer 1987 Feb 1;59(3):406-10.

16. Chlebowski RT, et al. Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer. J Clin Oncol 1990 Jan;8(1):9-15.

17. American College of Physicians. Parenteral nutrition in patients receiving cancer chemotherapy. Ann Intern Med 1989 May;110(9):734.

18. Gatenby RA. Potential role of FDG-PET imaging in understanding tumor-host interaction. J Nucl Med 1995 May;36(5):893-9.

19. von Ardenne M. Principles and concept 1993 of the Systemic Cancer Multistep Therapy (SCMT). Extreme whole-body hyperthermia using the infrared-A technique IRATHERM 2000 -- selective thermosensitisation by hyperglycemia -- circulatory back-up by adapted hyperoxemia. Strahlenther Onkol 1994 Oct;170(10):581-9.

20. Steinhausen D, et al. Evaluation of systemic tolerance of 42.0 degrees C infrared-A whole-body hyperthermia in combination with hyperglycemia and hyperoxemia. A Phase-I study. Strahlenther Onkol 1994 Jun;170(6):322-34.


POSTED BY
Dr. Mercola