103rd Annual AACR Meeting

gpawelski · April 2012

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.

gpawelski · April 2012

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.

luv_gardening · April 2012

Thanks Gregory for your informative posts. Always appreciated.

camillegal · April 2012

Gregory I think this is marvelous that u post this for all to read.

Joy u really understand this?

luv_gardening · April 2012

If only, Camille... I understand the general gist of it. I skim over the heavy biochemistry but still see roughly what they are doing, often after the second or third read and some Googling.

I particularly liked the three themes.

1. A renewed focus on the biochemistry of metabolism - this reflects the studies I've been reading relating to mitochondria and starving the cancer of nutrients and oxygen which is a special interest of mine.

2. Clear progress in field of tumor immunology - Vaccines, this may be the way to a cure or long term remission.

3. The growing recognition that human tumors exist as microenvironments and not isolated single cells. - Any new strategy opens up new possibilities. They've been looking at the cell level for so long, an expansion is needed.

gpawelski · April 2012

Joy has it pegged right! You skim over it and re-read it to get the general gist of it. You will eventually see what they are doing. Lots of Googling to understand the "thick-as-pea-soup" jargon.

For personalizing cancer therapy, metabolic profiles are essential. Taking aim at the metabolic reactions that fuels cancer growth. However, a report in the February Cell Metabolism showed that one metabolism-targeted cancer therapy will not fit all.

http://cancerfocus.org/forum/showthread.php?t=3615

It's good to see the resurgence of aggressive cancer vaccine research. Any criticism of this research would be typical of those that favor attempts to identify one-size-fits-all treatments through trial-and-error treatment. The choice of researchers to integrate promising insights and methods remains an essential component of new paradigms of cancer treatment.

http://cancerfocus.org/forum/showthread.php?t=3651

The capacity to study human tumor microenvironments distinguishes cell function analysis from other platforms in the field. The microclusters recapitulate the human tumor environment, while 3D advancement recreates the extracellular matrix. The platform studies cancer response to drugs within this microenvironment, enabling it to provide clinically relevant predictions to cancer patients.

http://cancerfocus.org/forum/showthread.php?t=3640

I've found that the AACR presentations are more informative than the ASCO meetings.

gpawelski · April 2012

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/2012/04/02/scitranslmed.3003380

103rd Annual AACR Meeting

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