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103rd Annual AACR Meeting


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103rd Annual American Association of Cancer Research (AACR) Meeting

By Robert Nagourney, MD, PhD

Rational Therapeutics, Inc.

Long Beach, CA.

The American Association of Cancer Research (AACR) meeting, held this year in Chicago, is the premier cancer research convention for basic and translational research. The AACR was the original cancer research organization that pre-dated its sister organization – the American Society of Clinical Oncology (ASCO). The focus of the AACR meeting is basic research and the presentations are often geared toward PhD level scientific discovery. I find this meeting the most informative for it provides insights into therapy options that may not arrive in the clinical arena for many years.

At the meeting, I again observed that the AACR presentations continue to diverge from those at the ASCO meetings. At this year’s meeting, I’m not sure I heard the word “chemotherapy” a single time. That is, all of the alphabet soup combinations that make up the sessions at ASCO are nowhere to be found at the AACR meeting. Instead, targeted agents, genomics, proteomics and the growing field of metabolomics reign supreme.

Several themes seemed to emerge:

That cancer patients are highly unique. In one presentation using phosphoprotein signatures to connect genetic features to phenotypic expression, the investigator conducted 21 phosphoprotein signatures and found 21 different patterns. This, he noted, reflected the "uniqueness" of each individual.

Additional themes included the growing development of meaningfully effective immune therapies. There was evidence of a renewed interest in tissue cultures as the best platform to study drug effects and interactions.

Although virtually every presentation began with the obligatory reference to genomic analysis, almost every one of them then doubled back to metabolism as the principal driver of human cancer.

Among the presentations was a discussion of NextGen genomic analysis, allowing an entire human genome to be sequenced within 24 hours. Mapping genetic elements has enabled investigators at the University of Pennsylvania to explore acute leukemia patients at diagnosis and at the time of recurrence. Based upon mutation analysis, different subsets of patients are observed. Mono and Oligo-clonal populations yield new subpopulations following cytoreductive therapy, wherein a small percentage of tumor cells survive and repopulate as the dominant clone.

The NextGen genomic analysis serves as the basis for new solid tumor studies in which breast biopsies are obtained, before and after therapy with aromatase inhibitors, to examine the clonality of the surviving populations.

William R. Sellers, MD, vice president of Novartis Institutes for BioMedical Research Oncology, described a high throughput robotic technology capable of conducting tens of thousands of combinatorial mixtures to determine drug interactions. What I found most interesting was the observation by this investigator that, “Cell culture remains the most effective means of testing drug combinations.” We agree wholeheartedly.

New classes of lymphoma therapies are in development that target B cell signaling pathways. A prototypic agent being Ibrutinib, the Bruton’s tyrosine kinase inhibitor. Additional developments are examining SYC as a target for small molecule inhibitors.

Our growing understanding of immune regulation is enabling investigators like James Allison to trigger tumor specific immunity. Agents like ipilumimab (AntiCTLA4), combined with other classes of small molecules and/or antibodies directed toward CD28, PD1, and ICOS regulation have the potential to change the landscape in diseases that extend from melanoma to prostate and breast.

The meeting had innumerable sessions and symposia that were geared toward or touched upon the field of metabolomics. As cells jockey for survival they both up- and down-regulate pathways essential to not only energy production but to the biosynthesis of critical metabolic intermediates. The regulation of PKM2 (pyruvate kinase isoenzyme) is now recognized as a pivotal point in the cell’s determination of catabolism (energy production), over anabolism (biosynthesis), with Serine concentrations playing an important regulatory role.

The PI3K pathway is an area of rapidly growing interest as new compounds target this key regulatory protein complex. Both selective and non-selective (pan PI3K) inhibitors are in clinical testing. Paul Workman’s group was honored for their seminal work in this and related areas of drug development. Robert Nagourney, MD, PhD, of Rational Therapeutics, reported his findings on the dual PI3K/mTOR inhibitor BEZ235 (Nagourney, RA et al Proc AACR, 2586, 2012).

The double-edged sword of immune response was deftly covered by Dr. Coussens who described the profound tumor stimulatory effects of T-cell, B-cell and Macrophage infiltration into the tumor microenvironment. Small molecules now in development that down-regulate macrophage signaling may soon show promise alone or in combination with other classes of drugs.

The RAS/RAF pathway becomes ever more complex as we begin to unravel the feedback loops that respond to small molecule inhibitors like Erlotinib or Vemurafanib. Investigators like Dr. Neal Rosen from Memorial Sloan-Kettering Cancer Center have long argued that simple inhibition at one node in a cascade of signaling pathways will absolutely change the dynamic and redirect up and down stream signals that ultimately overcome inhibition. Strategies to control these “resistance” mechanisms are being developed. Once again we find that simple genomic analyses underestimate the complexity of human systems.

Among the regulatory topics at this year’s meeting was a special symposium on the development and testing of multiple novel (non-FDA approved) compounds in the clinical trial setting. There will need to be a new level of cooperation and communication forged between academia, regulatory entities and the pharmaceutical industry if we are to move this process forward. I am encouraged by the early evidence that all three are recognizing and responding to that reality.

The themes of this year’s meeting included:

1. A renewed focus on the biochemistry of metabolism

2. Clear progress in field of tumor immunology

3. The growing recognition that human tumors exist as microenvironments and not isolated single cells.

We are particularly gratified by the last point.

Our EVA/PCD (functional profiling) focus on human tumor aggregates (microspheroids) isolated directly from patients as the most accurate models for chemotherapy selection and drug discovery appears to be gaining support.

Much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell’s metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time. Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.

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Abstract Number: 2856

Presentation Title: Functional profile of BEZ-235 activity in human tumor primary culture microspheroids by ex vivo analysis of programmed cell death (EVA/PCD)

Presentation Time: Monday, Apr 02, 2012, 1:00 PM - 5:00 PM

Location: McCormick Place West (Hall F), Poster Section 33

Poster Section: 33

Poster Board Number: 12

Author Block: Robert Alan Nagourney, Paula J. Bernard, Federico R. Francisco, Steven S. Evans. Rational Therapeutics, Inc., Long Beach, CA

Abstract Body:

Aberrant signaling through the phospho-inositol pathway via the gain of PI3K function or loss of PTEN is a hallmark of many malignancies. Drugs that inhibit this pathway offer novel therapeutic opportunities. The imidazoquinolone derivative, BEZ-235, reversibly inhibits signaling through PI3K & mTOR by competition at ATP binding sites. We used ex vivo analysis of programmed cell death (EVA/PCD) to examine the activity and clinical potential of BEZ 235 in human tumors isolated from 88 surgical tumor specimens. By interrogating drug effects in primary culture micro-spheroids, replete with vascular, stromal and inflammatory elements, the EVA/PCD platform can provide insights into cellular responses under native-state conditions. Lethal concentration 50% values (LC50’s), interpolated from dose response curves, were used to compare the activity of BEZ-235 by diagnosis using modified Z-scores. Comparisons between BEZ activity and related inhibitors of PI3K (LY294002), mTOR (Everolimus) & AKT (Phen B15-kindly provided by Dr. Peter Houghton) were conducted by Pearson-Moment. By rank order, BEZ-235 activity revealed upper gastrointestinal, breast, NSCLC and hematological malignancies to have the most favorable profiles, while renal, ovarian, colon and sarcoma specimens fell in the more resistant range. Pearson moments revealed high correlation coefficients (R values) for LY294002=0.56 (P =0.001); Everolimus=0.51 (P= 0.005) & Phen B15=0.89(P= 0.005) all consistent with BEZ-235’s known modes of action. As PI3K signaling is associated with inhibition of apoptosis, its up-regulation may confer collateral resistance to other stressors like growth factor withdrawal or cytotoxic drugs. Relationships between BEZ-235 and other classes of drugs are being examined to explore additional correlations and potential combination that could provide future therapeutic opportunities, as will be reported.

Supported in part by the Vanguard Cancer Foundation.

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Medscape Oncology

April 3, 2012 (Chicago, Illinois) — When it comes to predicting the risk for common diseases, including cancer, genome sequencing is not a magic bullet. It might be a valuable tool for people with a strong family history of a disease, but not for the vast majority of people, researchers report.

Genomic sequencing will never be a crystal ball that can reliably predict future health issues, explained researcher Bert Vogelstein, MD, Clayton Professor of Oncology and Pathology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.

"It cannot substitute for conventional risk-management strategies, including routine check-ups and lifestyle optimization," he said at a press briefing here at the American Association for Cancer Research 103rd Annual Meeting.

Dr. Vogelstein was summarizing the results of a study presented at the meeting and simultaneously published online April 2 in Science Translational Medicine.

The researchers analyzed data collected from thousands of twin-pair groups on the incidence of 24 diseases, including cancer and autoimmune, cardiovascular, genitourinary, neurologic, and obesity-associated conditions. They used mathematical models to predict disease risk.

For the majority of tested individuals, the results would be negative for most diseases. In addition, the predictive value of these negative tests would generally be quite modest, because "the total risk for acquiring the disease in an individual testing negative would be similar to that of the general population," according to the researchers.

Conversely, in the best-case scenario, the results show that the majority of people tested might be alerted to a clinically meaningful risk for at least 1 disease with whole-genome sequencing.

"We stand on the verge of a revolution, and advances in technology and sequencing that have immense implications for many fields of science," said Dr. Vogelstein. "But, as we all know from the recent revolutions in the Middle East, we can't always predict the final outcomes of revolutions."

He added that in genetics, and specifically in personalized medicine, many of the predictions have been based on qualitative arguments and anecdotal reports.

Positive and Negative Tests

A positive test result should indicate that a person has at least a 10% risk for disease. "That means 1 in 10 would develop the disease from all factors combined," he explained.

The usefulness of a negative test result "is in the eye of the beholder," Dr. Vogelstein noted. To be medically useful, the risk would have to be much lower than in the general population.

As an example, Dr. Vogelstein explained that 2% of those taking the test would get positive results for ovarian cancer. "That is 1 in 50 women, and that is the maximum — the best-case scenario," he said. "That can be useful for those women so they can have closer surveillance."

On the flipside, the other 98% of women would get a negative test. "Unfortunately, the negative test is not that informative because it only shows that they have a risk that is slightly lower than the general population," Dr. Vogelstein said.

These results were similar for the other diseases that the researchers looked at, although there were a few "outliers," Dr. Vogelstein explained. "In theory, with coronary heart disease — at least in males — it might be possible that many individuals in the population would have a positive test; this might put them on the alert for heart disease."

Cancer risk is influenced by both environmental and stochastic factors, which further dilutes the ability of whole-genome sequencing to predict disease risk.

To illustrate the limits of genetic testing, Dr. Vogelstein noted that currently, men have a 45% lifetime risk for cancer and women have a 38% lifetime risk. Having a negative test result would lower the risk to 32% to 42% in men and 27% to 36% in women, which is only a slight difference from that of the general population.

Dr. Vogelstein emphasized that information about the genome will not change these estimates, which "are made under the assumption that we are omniscient and understand the effects of every variant and their interactions with one another."

Benefit Seen for Some Conditions

Dr. Vogelstein and his team derived their estimates from 53,666 monozygotic twin pairs and clinical data from registries all over the world. Their analyses suggest that for 23 of the 24 diseases studied, the majority of individuals will receive negative test results, which will probably not be very informative.

With a negative test result, they estimate that the risk of developing 19 of the 24 diseases would be 50% to 80% of that in the general population, at a minimum.

For 13 of 27 disease categories, the researchers note that the majority of patients who would ultimately develop these diseases would not test positive, even in the best-case scenario. For 4 of the disease categories — thyroid autoimmunity, type 1 diabetes, Alzheimer's disease, and coronary heart disease deaths in men — genetic testing might be able to identify more than three quarters of people who subsequently will develop the disease.

Not Ready for Prime Time

A panel of discussants agreed with Dr. Vogelstein's conclusions and pointed out the implications of the study.

Timothy Rebbeck, PhD, professor of epidemiology at the University of Pennsylvania Perelman School of Medicine in Philadelphia, and editor-in-chief of Cancer Epidemiology, Biomarkers & Prevention, noted that "we are going to have to reconsider the value of genetic information and rethink new models and when this information is valuable and when it may not be."

He added that "what we are learning" from this study and previous research is that genetics might not be "the magic cure-all" for all things.

Thomas Sellers, PhD, MPH, executive vice president and director at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida, agreed "with the primary conclusion of this report," adding that this is a very "provocative" study that puts very important issues into perspective.

"Genome sequencing is not going away; there are questions that we have to look at," he said.

The third discussant, Olufunmilayo I. Olopade, MD, professor of medicine and human genetics and director of the cancer risk clinic at the University of Chicago School of Medicine in Illinois, pointed out how many researchers said the same thing about BRCA testing.

"I remember the argument we had almost 20 years ago about BRCA testing," she said. "Some thought nothing good could come out of that research..., now it has been adopted," Dr. Olopade said. "Many women died from ovarian cancer, and we could have prevented it if we had known."

She emphasized that "we are now just beginning our understanding," and that to have an impact on prevention, "we need to have a more elaborate approach."

"I think that genome sequencing can improve public health, but we need to know how we are we going to do it," she said. "We are not there yet, it's not ready for prime time.

American Association for Cancer Research (AACR) 103rd Annual Meeting. Presented April 2, 2012.

Sci Transl Med. Published online April 2, 2012.

http://stm.sciencemag.org/content/early ... ed.3003380

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  • 2 weeks later...

Dr. Robert Nagourney

Medical and Laboratory Director

Rational Therapeutics, Inc.

Long Beach, California

In the March 8 issue of the New England Journal of Medicine, investigators from London, England, reported disturbing news regarding the predictive validity and clinical applicability of human tumor genomic analysis for the selection of chemotherapeutic agents.

As part of an ongoing clinical trial in patients with metastatic renal cell carcinoma (the E-PREDICT) these investigators had the opportunity to conduct biopsies upon metastatic lesions and then compare their genomic profiles with those of the primary tumors. Their findings are highly instructive, though not terribly unexpected. Using exon-capture they identified numerous mutations, insertions and deletions. Sanger sequencing was used to validate mutations. When they compared biopsy specimens taken from the kidney they found significant heterogeneity from one region to the next.

Similar degrees of heterogeneity were observed when they compared these primary lesions with the metastatic sites of spread. The investigators inferred a branched evolution where tumors evolved into clones, some spreading to distant sites, while others manifested different features within the primary tumor themselves. Interestingly, when primary sites were matched with metastases that arose from that site, there was greater consanguinity between the primary and met than between one primary site and another primary site in the same kidney. Another way of looking at this is that your grandchildren look more like you, than your neighbor.

Tracking additional mutations, these investigators found unexpected changes that involved histone methyltransferase, histone d-methyltransferase and the phosphatase and tensin homolog (PTEN). These findings were perhaps among the most interesting of the entire paper for they support the principal of phenotypic convergence, whereby similar genomic changes arise by Darwinian selection. This, despite the observed phenotypes arising from precursors with different genomic heritages. This fundamental observation suggests that cancers do not arise from genetic mutation, but instead select advantageous mutations for their survival and success.

The accompanying editorial by Dr. Dan Longo makes several points worth noting. First he states that “DNA is not the whole story.” This should be familiar to those who follow my blogs, as I have said the same on many occasions. In his discussion, Dr Longo then references Albert Einstein, who said “Things should be made as simple as possible, but not simpler.” Touché.

I appreciate and applaud Dr. Longo’s comments for they echo our sentiments completely. This article is only the most recent example of a growing litany of observations that call into question molecular biologist’s preternatural fixation on genomic analyses. Human biology is not simple and malignantly transformed cells more complex still. Investigators who insist upon using genomic platforms to force disorderly cells into artificially ordered sub-categories, have once again been forced to admit that these oversimplifications fail to provide the needed insights for the advancement of cancer therapeutics. Those laboratories and corporations that offer “high price” genomic analyses for the selection of chemotherapy drugs should read this and related articles carefully as these reports portend a troubling future for their current business model.

All laboratory platforms are subject to “sampling errors”. That is, the tissue procured may not be reflective of the overall biology of the disease. This however is compounded by laboratory platforms that use FNA’s to measure genes or other “analytes” that are not functional parameters of the disease process, in all its complexity. These are instead mere reflections of the disease process, as it were, a veneer of information gleaned from the most superficial surface.

To address smapling errors, we prefer large specimens which are assessed in their native state, not propagated or sub=cultured (thereby avoiding addtional artifacts). These are preferably obtained from metastatic sites, which often reflect greater degeees of resistance over the tumor primaries, giving us the best “shot” at both. We know from extensive clinical experience that many (most) patients that have responses to systemic therapy, have overall improvement with only a minority having true “mixed” responses. We also know that the tumors and their metastatic lesions share biologic similarities that provide useful insights into the tumor’s relative sensitivity to drugs. Even still, the subsequent re-growth of tumors, may reflect clonal expansion resulting from the elimination of the more sensitive tumors and emergence of a new dominant clone. To address this, we will often re-biopsy and re-dedicate our efforts to controlling the second or subsequent clones.

All of these theoretical issues are hurdles to be overcome. They contribute to the fact that, although our lab analyses consistently double objective response rates, they are not perfect predictors. It is extremely important to remember that all the medical oncologists in practice today confront all of these same issues (heterogeneity, clonal divergence, differeing biology from primary to met, etc) yet they select drugs and combinations with absolutely no guidance whatsover!

http://robertanagourney.wordpress.com/2 ... s/#respond

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To better understand the signaling pathways active in sarcomas, researchers at Moffitt Cancer Center used state-of-the-art mass spectrometry-based proteomics to characterize a family of protein enzymes that act as "on" or "off" switches important in the biology of cancer. The tyrosine kinases they identified, the researchers said, could act as "drivers" for the growth and survival of sarcomas.

Sarcomas are relatively rare forms of cancer. In contrast to carcinomas, which arise from epithelial cells (in breast, colon and lung cancers, for example), sarcomas are tumors derived from bone, fat, muscle or vascular tissues.

"Sarcomas are rare, diverse malignancies that arise from connective tissues," said study lead author Eric B. Haura, M.D., program leader for Experimental Therapeutics. "We hypothesized that we could identify important proteins that drive the growth and survival of these poorly understood sarcomas using an approach to characterize signaling proteins using mass spectrometry."

According to Haura, whose lab focuses on signaling pathways in cancer and understanding the role of kinases, protein phosphorylation plays a significant role in a wide range of cellular processes and is commonly disrupted in diseases such as cancer. The study approach is novel by engaging proteomics, an emerging and increasingly powerful approach to study proteins in disease in a more global and unbiased manner.

In this study, the Moffitt researchers identified 1,936 unique tyrosine phosphorylated peptides corresponding to 844 unique phospho-tyrosine proteins and found 39 tyrosine kinases in sarcoma cells. Of the 99 tyrosine kinases present in the human genome, the research team identified peptides corresponding to nearly 40 percent of the tyrosine kinome.

"Tyrosine kinases play an important role in controlling the hallmarks of cancer, and they have a proven track record as druggable targets for cancer treatment. Our goal was to produce a 'landscape' of tyrosine phosphorylated proteins and tyrosine kinases prioritized for subsequent functional validation," Haura said. "In our study, we identified numerous tyrosine kinases that can be important for cellular signaling in human sarcomas that could drive the natural progression of sarcoma and, therefore, could be targeted by small molecule inhibitors aimed at altering sarcoma progression."

Questions remain, however, about which, if any, of the 40 tyrosine kinases the researchers identified in sarcoma tumor cell lines act to regulate sarcoma tumor cell growth and tumor survival.

"The answers to this question can help prioritize which potential targets to examine further, including advancement into trials of patients with advanced sarcoma," explained Haura. "As a first step, we screened sarcoma cell lines against a number of inhibitors selected, all based on the tyrosine kinases we identified, and identified some active drugs."

While the researchers found kinases in sarcoma cells that deserved further study, they also concluded that the sarcoma cells tested expressed multiple tyrosine kinases. That great number may limit the effectiveness of targeted agents.

"We think this approach could hold promise in profiling tumors directly from patients and can complement existing genetic data on sarcomas. Our results show this is feasible in tumor tissues, and we hope to advance this further by directly studying additional tumors from sarcoma patients."

Their study appeared in the issue of Cancer Research published by the American Association for Cancer Research (AACR).

Source: H. Lee Moffitt Cancer Center & Research Institute

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KRAS Gene Mutation and Amplification Status Affects Sensitivity to Antifolate Therapy

Patients with lung cancer and KRAS mutation responded well to antifolate therapy. Response linked to downregulation of KRAS expression. Downregulation may render cells more susceptible to chemotherapeutic drug.

KRAS mutation and amplification status predicts sensitivity to antifolate therapies in Non Small Cell Lung Cancer

Presenter: Sarah Bacus, Ph.D.

Abstract Number: LB-449

Diarmuid M. Moran, Patricia Trusk, Scott A. Shell, D. Ross Camidge, Robert C. Doebele, Eamon Berge, Mark Vincent, Sarah Bacus. Quintiles Transnational Corp., Westmont, IL, University of Colorado, Denver, CO, University of Western Ontario, London, ON, Canada.


Somatic genetic mutation in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene has been linked to poor prognosis and resistance to various targeted therapeutics in Non Small Cell Lung Cancer (NSCLC). Therapeutic strategies that target tumors harboring these mutations represent an unmet medical need. In this study, we investigated the relationship between antifolate sensitivity and KRAS mutation/amplification status in NSCLC.

Human NSCLC cell lines (KRAS wild type, KRAS mutant non-amplified and KRAS mutant amplified) were treated with Methotrexate (MTX) or Pemetrexed (PEM) and assayed for proliferation. In these studies, KRASwt (wildtype) and KRASmut (mutant) amplified cells showed resistance to MTX treatment (IC50 >10μM). In contrast, growth of all KRASmut non-amplified cell lines studied was inhibited with MTX treatment (IC50 <100nM). Similar effects were observed for PEM in this study. Interrogation of the NCI Developmental Therapeutics Program drug screen database for the relationship between KRAS mutation status and drug efficacy also revealed a similar trend in other NSCLC cell lines for MTX and other anti-folates. qPCR analysis demonstrated a dramatic downregulation of KRAS gene expression in KRASwt and KRASmut cells with antifolate treatment. However, KRAS gene expression was less affected in antifolate treated KRASmut amplified cells. Co-treatment of KRASmut cells with antifolates and hypoxanthine/thymidine (which compensate for folate pathway inhibition) prevented downregulation of KRAS gene expression and rescued KRASmut cells. qPCR array analysis of miRNA expression in antifolate treated cells revealed increased expression of specific miRNAs, including miR-181c, with treatment compared to untreated controls. Transfection of a miR-181c mimic led to downregulation of KRAS gene expression in cells. Furthermore, antagomirs targeting miR-181c partially inhibited the downregulation of KRAS by antifolates. Importantly, we present clinical data describing rapid and durable radiographic responses in KRAS mutant NSCLC cancer patients.

Collectively, these studies identify higher sensitivity to antifolates in KRASmut non-amp NSCLC cell lines. Antifolate therapies decrease KRAS gene expression in KRASwt and KRASmut but do not do so in KRASmut amplified cells. We propose that decreased KRAS gene expression is detrimental to KRASmut cells due to their dependency on this survival pathway. We also propose that decreases in KRAS gene expression are mechanistically linked to stress (folate inhibition) induced miRNA expression which target KRAS gene expression. Overall, antifolates represent a novel method to target KRAS and as such should be investigated further for use in this subtype of NSCLC. As clinical evidence emerges, both KRAS mutation and amplification status should be incorporated for patient stratification prior to antifolate treatment.

This study was funded by the Quintiles Translational Research and Development Group; no external funding was used to finance the research.

Source: American Association for Cancer Research

Cell-lines are useful for experimentation in labs as they are always available to researchers as a product and do not require harvesting (acquiring of tissue from a host) every time cells are needed in the lab.

Problem is, cell-lines do not predict for disease or patient specific drug effects. If you kill lung cancer cell-lines with a given drug, it doesn't tell you anything about how the drug will work in real world, clinical lung cancer (real-world conditions). But you can learn certain things about general drug biology through the study of cell-liines.

As a general rule, studies from established cell-lines (tumor cells that are cultured and manipulated so that they continue to divide) have proved worthless as models to predict the activity of drugs in cancer. An established cell-line is not reflective of the behavior of fresh tumor samples in primary culture, much less in the patient.

Cell-lines don't recapitulate drug response patterns which exist in the body. You get different results when you test passaged cells compared to primary, fresh tumor. For drug selection, it is better to directly remove tumor microclusters straight from the body and immediately test them, before they change.

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The exon 18 mutation known as a G719X can respond to Tarceva, even though a patient may be EGFR negative. Fortunately, some physicians don't follow the so-called rules of chasing gene mutations. If you have the EGFR mutation, give it out. If you don't have the EGFR mutation, don't give it out.

When it comes to "drug selection" though, the molecular investigator can only measure those analytes in paraffin wax that they know to measure. If you are not aware of and capable of measuring a biologically relevant event, you cannot seek to detect it. If you don't know about the G719X, you don't know what to look for, and you aren't going to find it. The same goes for all the other loads of mutations clinicians don't know about, ABC, XYZ, you name it.

Originally, Xalkori was developed for patients who carried the CMET mutation. However, they later found a responding subpopulation that was actually carrying an unrecognized ALK gene rearrangement. Nexavar was originally evaluated for the treatment of BRAF mutation positive patients. Yet it was the drug's cross reactivity with the VEFG tyrosine kinases that lead to broader clinical applications.

The point is, each of these phenomena represents accidental successes. The lessons learned from this is that cancer biology is complex. Actually, it doesn't matter why Tarceva worked, so long as it did. I understand that there is reason to believe that the more potent irreversible EGFR/HER2 dual inhibitor HKI-271 may be even more selective for this point mutation.

The premise of the functional (cytometric) profiling platform is that the observation of a biological signal identifies a candidate for therapy whether we understand or recognize the target. Were it not for the clinical observation of response in patients, investigators would been unlikely to make the discoveries that provide such good clinical responses.

When cell function analysis first identified lung cancer as a target for Iressa, and began to administer the closely related Tarceva to lung cancer patients, neither Lynch nor Paez had identified the sensitizing EGFR mutations. That had absolutely no impact upon the excellent responses that were observed with cell function analysis.

It didn't matter why it worked, but that it worked. Might we not use functional analytical platforms (functional cytometric profiling) to gain insights into the next, and the next, and the next generation of drugs and therapies that target pathways like MEK, ERK, SHH, FGFR, PI3K, etc.?

While it may be nice to think that driver mutations are 90% predictive of a response, sometimes the genetic signal may not be the driver mutation. Other signaling pathways, like passenger mutations, could be operative.

It turns out that most mutations in cancers are passengers. It had been thought by molecular scientists that driver mutations are the ones that cause cancer cells to grow, whereas passengers are co-travellers that make no contribution to cancer development.

However, buried among them are much larger numbers of driver mutations than was previously anticipated. This suggests that many more genes contribute to cancer development than was thought.

Cells speak to each other and the messages they send are interpreted via intracellular pathways. You wouldn't know this using analyte-based genomic and proteomic methodologies. However, functional (cytometric) profiling provides the window. It can test various cell-death signaling pathways downstream.

While most scientists use genomic or proteomic platforms to detect mutations in these pathways that might result in response to chemicals, functional (cytometric) profiling platforms have taken a different tack. By applying functional analysis, to measure the end result of pathway activation or deactivation, they can predict whether patients will actually respond.

The functional (cytometric) profiling platform has the capacity to measure genetic and epigenetic events as a functional, real-time adjunct to static genomic and proteomic platforms.

As virtually every presentation at the 2012 AACR meeting made obligatory reference to genomic analysis, almost every one of them then doubled back to metabolism as the principal driver of human cancer.

Source: Cell Function Analysis

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Metabolomics is a newly emerging field of "omics" research concerned with the comprehensive characterization of the small molecule metabolites in biological systems. It can provide an overview of the metabolic status and global biochemical events associated with a cellular or biological system.

An increasing focus in metabolomics research is now evident in academia, industry and government, with more than 500 papers a year being published on this subject. Indeed, metabolomics is now part of the vision of the NIH road map initiative (E. Zerhouni (2003) Science 302, 63-64&72).

Many other government bodies are also supporting metabolomics activities internationally. Studying the metabolome (along with other "omes") will highlight changes in networks and pathways and provide insights into physiological and pathological states.

The concept of Systems Biology and the prospect of integrating transcriptomics, proteomics, and metabolomics data is exciting and the integration of these fields continues to evolve at a rapid pace. Developments in informatics, flux analysis and biochemical modeling are adding new dimensions to the field of metabolomics.

To be able to walk from genetic or environmental perturbations to a phenotype to a specific biochemical event is exciting. Metabolomics has the promise to enable detection of disease states and their progression, monitor response to therapy, stratify patients based on biochemical profiles, and highlight targets for drug design.

The metabolomics field builds on a wealth of biochemical information that was established over many years.

The Metabolomics Society


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Cancer Survivors: Nearly Half Eventually Die of Something Other than Cancer

Nearly half of cancer survivors die from other disorders, according to a study reported at the AACR Annual Meeting (Abstract LB 339). Researchers examined data on 1,807 cancer survivors who participated in the 1988–1994 and 1999–2004 National Health and Nutrition Examination Surveys (NHANES). They were followed for a median of seven years, during which time 776 of them died.

Fifty-one percent died of cancer and 49% from other causes. Cardiovascular disease was responsible for 69% of the non-cancer deaths. Chronic lower respiratory diseases claimed 15% of their lives, and Alzheimer's disease and diabetes were each responsible for 4% of non-cancer deaths.Said Yi Ning, MD, ScD, Associate Research Member at the Virginia Commonwealth University Massey Cancer Center: "Cancer, in general, is regarded as one of the most life threatening diseases. In the past decade, with the application of advanced scientific and medical technologies for cancer early detection, prevention, and treatment, cancer survivors are now living much longer and do not die directly from cancer, but rather, from other diseases and complications. It therefore becomes increasingly important to understand major causes of death among cancer survivors to improve the quality of life and prolong life expectancy of cancer survivors. Our results showed that although cancer is the major cause of death among cancer survivors, approximately half of participants died from other diseases and complications, such as cardiovascular and respiratory diseases. Clinicians and cancer survivors should pay attention to the prevention and treatment of other diseases and complications."

Oncology Times: 25 May 2012 - Volume 34 - Issue 10 - p 16

By analyzing non-cancer deaths among cancer patients, it becomes clear that orthodox therapies often do more harm than good. For example, cancer treatment can damage the heart and cause deaths from heart failure. This means fewer deaths from cancer. Analysis of the records of 1.2 million cancer cases in the Surveilance, Evaluation and End Results (SEER) database showed that non-cancer deaths accounted for 21 - 37% of all deaths. The authors attributed this effect to the damage caused by cancer treatment (mainly radiotherapy and chemotherapy).

Some common chemotherapeutic agents (paclitaxel, doxorubicin, and trastuzumab) can trigger hypertension or problems with the heart, such as arrhythmias, congestive heart failure, or bradycardia. There are some, like 5-FU [fluorouracil] and Xeloda [capecitabine], that can cause chest pains, resulting from spasms of the arteries that go to the heart. Many patients on chemotherapy become anemic, and that can trigger further cardiac complications. Other agents affect the kidneys, sometimes to the point of requiring dialysis. In addition, because many patients on chemotherapy are immunocompromised, pulmonary infections are quite common.

It's interesting. Results from clinical trials indicated that most "targeted" therapies of today do not cause the usual side effects associated with cancer treatment, such as hair loss and fatigue. However, other side effects may occur with these drugs, including rash, hand/foot syndrome (sores on the hands and feet) and an increased risk of heart attack and stroke. Exchanging one set of side effects with another set of side effects?

Bacterial infections (with pseudomonas being a very common offender) have been a recognized risk of chemotherapy since the 1940's. In fact, the number one cause of chemotherapy-related mortality (save for the likely probability that it induces mutations in genetically unstable cancer cells to produce a more aggressive cancer cell) is infection, resulting from immunosupression. There are several mechanisms of immunosuppression, the most obvious being the predictable reduction in the white blood cell count following most forms of chemotherapy. The main justification of having medical oncology be a medical specialty unto itself is the expertise it requires to push the envelop with toxic drugs to kill the tumor without killing the patient. The second mechanism of immunosuppression is a reduction in lymphocytes and plasma cells, which also assist in fighting infections.

It's analogous to the old medical specialty of syphilology. There was a big medical specialty called syphilology which existed because of the expertise it took to give toxic cocktails of the various (mostly ineffective drugs). The formulas were quite complicated, but they persisted until the discovery of penicillin, which finally killed off not just the syphillis spirochete but also the specialty of siphilology. I would hopefully expect that something like this will happen with medical oncology, and I would be thrilled if it happened while I was still around to see it.

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