American Association of Cancer Research 2012

In my last blog, I described my recent attendance at the American Association of Cancer Research (AACR) meeting held in Chicago. This 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. 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.

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. We reported our 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 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.

The Avastin Saga Continues

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.