The Future of Cancer Research

The American Association for Cancer Research meeting held April 6 – 10 in Washington DC, provided a scientific perspective on oncologic developments. As opposed to the more clinical American Society of Clinical Oncology (ASCO), basic scientists attend this meeting, a large percentage of who are PhDs. The conference affords these investigators the opportunity to discuss their basic research and to present methodology workshops. The meeting also provides an early overview of the general direction that cancer research will be taking over the coming years.

While ASCO reports what we’ve recently done, AACR reports what we will be doing.

There were several overarching themes at this year’s meeting, the most prominent of these being the remarkable strides in immunologic therapy. Numerous investigators reported novel developments in the field. Where the immune system used to present as an insurmountable barrier of complexity, today we have dissected specific response elements and immune suppressive pathways that offer unique opportunities for therapy. Immunologic therapeutics are now specializing into sub-domains.

One productive area reflects de-repression. The most mature example being ipilimumab, the monoclonal directed against CTLA-4. This broadly expressed T-cell repressor molecule can be de-repressed resulting in significant anti-tumor activity, but with moderate to severe toxicity. The inhibition of PDL-1 is more selective and therefore less toxic, it has provided responses in melanoma, NSCLC and other diseases.

Earlier stage research is also focusing on tryptophan metabolism and the role of indoleamine 2, 3-dioxygenase. Manipulations of dendritic cells, altering prostaglandin TGF beta, IL-10, IL-6 and the STAT3 signaling pathway are also areas of active investigation. Additional studies included transferred receptors, like the CD19-related chimeric antigen receptor work and the targeting of co-stimulatory molecules like CD28.

Among the most striking observations in this field is the role of the human immune system and the tumor microenvironment in tumor promotion. Immunologists are rapidly learning that cancer is much more than just cancer cells.

The second broad concept that occurred repeatedly was the growing recognition of cancer as an organismal disease. When we realize that circulating tumor cells can be identified in the blood stream and bone marrow of virtually all cancer patients, even in many of those with putative in-situ disease, it becomes evident that invasive malignancies occur as the intersection of a primed cell and a receptive microenvironment. In light of our laboratory’s long held belief in the concept of native state microspheroids as predictive models (as used in our EVA-PCD® platform), this theme was highly appealing.

The developing principle that most closely approximated our work was captured in a special symposium organized by Charles Sawyer, president-elect of AACR. The topic of this well-attended session was the “N of 1.” That is, every patient is his or her own clinical trial. Nothing could be closer to our own work. During this session, two new directions for cancer research were described. The first, described as the “P2G,” was characterized by “exceptional responses.” The developing program through the NCI will collect tissue samples from patients who have had especially good responses from therapy and attempt to drill down on the mechanism of response. This exemplifies the phenotype to genotype (P2G). The second concept was the “G2P.” This reflects genomic screening, leading to the identification of lead targets followed by the administration of treatments. This “genotype to phenotype” approach is the one more closely aligned with investigations being conducted today at major centers here and abroad.

It is the exceptional response (phenotype to genotype) approach that most resonated. After all we have pioneered the field of phenotypic analysis. To wit, the use of human tissues in primary culture can offer the opportunity to explore literally dozens of exceptional responses in every patient’s tissues. A hit could provide insights for mechanistic discovery. It is my hope that this P2G paradigm will take hold – I see it as the most productive direction.

Cancer as a Metabolic Disorder

I received an inquiry via Twitter “Has anyone thought about using a sugar medium (similar to PET scans) to deliver chemo drugs?”

Although no one would use PET scans nor the PET reagents as therapy, the question is actually profound. There is a growing recognition that cancer is not a genetic disease but instead a metabolic disorder. One could not attend a lecture at the American Association of Cancer Research without there being reference to Otto Warburg’s 1956 paper “On the Origin of Cancer Cells” that described the metabolic basis of human malignancy.

Despite our myopic focus on cancer genomics, there is a growing recognition that cancer represents dysregulated energy metabolism. The high utilization of glucose, a hallmark of malignantly transformed cells, (and the target of PET scan diagnostics), in part reflects the process of aerobic glycolysis, whereby cells provided ample oxygen nonetheless eschew the efficiency of mitochondrial oxidative phosphorylation in favor of seemingly inefficient lactate production.

Into this new realm of biochemically driven developments, a growing number of therapeutic agents that target glucose metabolism are finding their way into the clinic. To the dismay of some, the mutations that our molecular biologists identify are increasingly found to represent intermediates of cellular metabolism, forcing many to go back to relearn biochemistry. Thus, the avidity for glucose represented by uptake of the PET scan reagent F18 fluorodeoxyglucose by tumor cells, is a diagnostic application of what, in the future, may provide meaningful therapeutic opportunities.

Is There a Role for Maintenance Therapy in Cancer Treatment?

There is a long tradition of maintenance therapy in pediatric oncology. Children with acute lymphoblastic leukemia uniformly receive three stages of therapy: induction, consolidation, and finally maintenance. The maintenance stage consists of weekly, or even daily therapies.

The historical experiences of relapse in this population lead investigators to consistently expose these patients to drugs for a period of years. Despite the apparent success of this approach in childhood cancers, long-term maintenance therapy did not gain popularity in adult oncology. Why?

There are probably several reasons. One reason is that childhood leukemia is among the most chemo-responsive diseases in medicine. As such, there are many active drugs available for treatment and many non-cross-resistant maintenance schedules that can be employed.

A second reason is the relative tolerability of drugs like oral thioguanine or mercaptopurine that are used in chronic maintenance therapy. By contrast adult tumors rarely achieve complete remissions. The number of active drugs has historically been very limited and the tolerance of long-term treatments characteristically poor.

Despite this, there is an appealing rational for maintenance therapy. Once we recognized and incorporated the tenents of apoptosis and programmed cell death into cancer management, we were forced to reconsider many of the principles of older treatment protocols.

Conceptually, maintenance allows for a cytotoxic exposure when the cell enters a “chemosensitive” period in its life cycle.  Cancer cells that are “out surviving” their normal counterparts often do so in a quiescent stage (G0 Gx). In order to capture these cells, drugs must be present in the body when these cells awaken from their dormancy. As we have now achieved increasingly durable remissions in diseases like breast cancer, small cell lung and ovarian, we are confronting patients in long-term complete remission. When you add to this newfound population the availability of comparably mild agents, like the low dose Gemcitabine/Cisplatin doublet, we now have at our disposal active drugs that can be safely continued for long periods of time.

Using laboratory selection to identify first line (induction), second line (consolidation) and finally third line (maintenance) schedules, we can now offer our patients well-tolerated combinations that offer the hope of more durable remissions.

The GOG 178, in which continued taxol dosing provided more durable remission in ovarian cancer, provided the first inklings of this. Unfortunately, taxol is toxic. And the more durable remissions came at an increasingly high price: neuropathy, myelosuppression, alopecia, fatigue and malaise, which greatly limited the utility of this approach. Yet it does not limit its theoretical attractiveness as we continue to develop targeted agents with more selective activity and modified toxicity profiles. We anticipate maintenance therapies will become more widespread.

Based upon our experiences to date, we are successfully using this approach with our patients who achieve good clinical remissions.

You can find more information about our use of maintenance therapy, in Chapter 14 of the book Outliving Cancer.

This blog was originally posted in August 2011.

Cancer Patients: Cure the Curable, Treat the Treatable and Avoid Futile Care

During my interview with Jeff Michaels on the March 28, 5:00 P.M. Fox News, we explored the themes of my current book, Outliving Cancer. One of the points that most interested my interviewer was the appropriate use of our laboratory platform for the selection of therapy. He asked, “Are there some patients for whom there is no cure?” I responded by explaining what it is, that our laboratory test is designed to do: “Cure the curable, treat the treatable, and avoid futile care.” Jeff Michaels stopped me and asked that I might repeat what I had just said. It seemed that my succinct description resonated.

However simple this distillation of our work may seem, I realized it was actually rather profound. After all, we are confronting an escalating crisis in medicine. How do we meet the needs of a growing population of cancer patients with shrinking resources? How do we allocate treatments to those most likely to respond and finally, how do we avoid the misadventures of toxic and ineffective therapies for those destined to fail chemotherapeutic intervention? On every level, laboratory models can assist us. For those patients with early stage breast cancer, ovarian cancer, small cell lung cancer, non-Hodgkin lymphoma and many leukemias, the expectation of a cure is well within our reach. These patients must receive the very best treatments from the start.

The larger population of patients we confront are those with diseases like gastric, colon, non-small cell lung, recurrent breast, recurrent ovarian or sarcoma for whom cures are less likely and effective therapies must be tolerable so that they can provide benefit without undue toxicity. These are the patients for whom cancer can become a “chronic disease.”

Finally, we must all confront patients for whom treatments offer little likelihood of benefit, yet significant risks of toxicity. These heavily pretreated patients, or those who present with refractory malignancies like pancreatic, kidney cancer or melanoma – represent a special subset. Here the role of the physician is to decide that almost Shakespearean question, “To treat or not to treat.”

This is a particularly delicate circumstance as it forces the doctor, the patient and the family to confront the most difficult question of all, “Am I dying?” The answer is “maybe.” Without seeming flip, every patient no matter what diagnosis, has some chance of response to therapy. If we examine the performance characteristic of our laboratory analyses, they consistently double response rates. With this group however a doubling of response rate may still provide a rather low likelihood of meaningful benefit. If the laboratory finds drug resistance in this group, it is a near certainty that the patient will not respond.

However distressing this data may be, it may be comforting to know that the patient has left no stone unturned. For those patients where a treatment appears active, despite their diagnosis or treatment history, then the discussion surrounding tolerance, toxicity and realistic likelihood of benefit can be undertaken intelligently. This is the embodiment of rational therapeutics.