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.

A New Target in Breast Cancer Therapy

In many ways the era of targeted therapy began with the recognition that breast cancers expressed estrogen receptors, the original work identified the presence of estrogen receptors by radioimmunoassay. Tumors positive for ER tended to be less aggressive and appear to favor bone sites when they metastasized. Subsequently, drugs capable of blocking the effects of estrogen at the estrogen receptor were developed.  Tamoxifen competes with estrogen at the level of the receptor. This drug became a mainstay with ER positive tumors and continues to be used today, decades after it was first synthesized.

Recognizing that some patients develop resistance to Tamoxifen, additional classes of drugs were developed that reduced the circulating levels of estrogen by inhibiting the enzyme aromatase, this enzyme found in adipose tissue, converts steroid precursors to estrogen.  Despite the benefits of these classes of drugs known as SERMS (selective receptor modulators), many patients break through hormonal therapies and require cytotoxic chemotherapy.

With the identification of HER-2 amplification, a new subclass of breast cancers driven by a mutation in the growth factor family provided yet a new avenue of therapy – trastuzumab (Herceptin). For HER-2 positive breast cancers Herceptin has dramatically changed the landscape. Providing synergy with chemotherapy this monoclonal antibody has also been applied in the adjuvant setting offering survival advantage in those patients with the targeted mutation.

Reports from the San Antonio breast symposium held in Texas last December, provide two new findings.

The first is a clinical trial testing the efficacy of pertuzumab. This novel monoclonal antibody functions by preventing dimerization of HER-2 (The target of Herceptin) with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross talk between receptors is abrogated and downstream signaling in squelched.

The second important finding regards the use of everolimus. This small molecule derivative of rapamycin blocks cellular signaling through the mTOR pathway. Combining everolimus with the aromatase inhibitor exemestane, improved time to progression.

While these two classes of drugs are different, the most interesting aspect of both reports reflects the downstream pathways that they target. Pertuzumab inhibits signaling at the PI3K pathway, upstream from mTOR. Everolimus blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway. Thus, these are in truest sense of the word, breakthroughs in metabolomics.

Cancer Survivorship

Some of you may have read the January report from the American Cancer Society (ACS) that described a decline in U.S. cancer death rates by 1.8 percent per year in men and 1.6 percent per year in women during the period between 2004 to 2008.

These encouraging results have been touted as evidence of success in the war on cancer. The war on cancer itself began in December 1971, when then president Richard Nixon established a national priority to conquer this disease. Since that time, we have dedicated more than $200,000,000,000 to this effort and published literally millions of articles on the topic. Despite these efforts and tremendous resource allocations, the focus of this research effort, i.e. treatment of advanced malignancies, has provided limited successes.

If we drill down onto the ACS statistics we find that most of the survival changes reflect earlier detection and the successful application of cancer screening. Mammograms, colonoscopies, the use of PSA and the growing application of screening CT scans for lung cancer detection have, and will continue to have, a favorable impact on cancer statistics.

This is the good news. The bad news is that our success in treating advanced disease is almost non-existent. While there have been slow migrations in a favorable direction for the five-year survival rates in some malignancies, the big killers like lung and GI, have shown extremely limited progress. There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase our rate of success.

First, we need to incorporate systems biology into cancer research. As opposed to analyte-based approaches like genomics that unravel one finding at a time, the field of biosystematics examines human cancer through the lens of interacting networks.

Second, we need to redouble our efforts in the study of basic metabolism and the growing field of metabolomics.

Third, we need to revamp the clinical trial process. Were investigators incentivized to achieve greater clinical successes, there were be fewer failed Phase II and Phase III trials. Contrary to the business world where success is rewarded, academic physicians today receive the same compensation for every patient treated, whether the intervention is successful or not. This has the unintended consequence of encouraging physicians to accrue patients to clinical trials with no focus on effective therapies. While it may be gratifying to the trialists to have successes, they receive the same compensation for their failures. Clinical investigators need skin in the game.

Finally, the regulatory environment is currently over-restrictive. The process should allow investigator-initiated efforts with more lenient review processes. The current environment that punishes dedicated physicians for stepping out of the established guideline therapies is thwarting progress and frightening dedicated investigators out of the field. Good faith efforts on the part of physicians using new drugs and combinations that document successes and failures, could unleash an army of clever physicians to utilize novel approaches to advance new therapies with little additional cost.

Lethal diseases, like advanced cancer, pose hurdles that require novel trial designs and less stringent controls. Patients confronting these illnesses should be allowed to receive therapies and should be granted the dignity to determine their own risk-benefit ratios when they confront life and death decisions. Simple consent forms could make available effective treatments while pharmaceutical corporations should be encouraged to provide drugs under the auspices of these patient-driven developmental trials.

While we applaud the discoveries of our colleagues in the field of genomics, and their analyte-driven platforms, we forget at our peril that medicine and most of its discoveries have been observational.