Melanoma, the Immune System, and Targeted Therapies

For those of you who have been following the recent news coming from the American Society of Clinical Oncology (ASCO) held in Chicago, you have heard of the breakthroughs for the treatment of malignant melanoma.

Melanoma, the most lethal form of skin cancer, arises as a pigmented lesion (mole or large freckle), generally in sun-exposed areas. Though curable in its earliest stages, once these malignancies disseminate, they can be the most aggressive and hard to treat cancers known to oncologists. That is, until recently when two important discoveries were made.

The first discovery actually dates back many years. It turns out that melanoma is one of those cancers that occasionally, spontaneously, regresses and that a subset of patients respond to interferon (an immune protein). This suggested a role for the immune system.

The next piece of evidence came from work in the 1980s, conducted by Steven Rosenberg, MD, PhD, at the National Cancer Institute. Using a genetically engineered human protein (interleukin 2-IL2), these investigators reported responses in patients with metastatic melanoma. Again, an immune component to this dreaded disease.

Fast-forward two decades. Investigators unraveling the complexities of human immunity realized that the cancer cells weren’t being recognized and effectively controlled by lymphocytes. Something was dampening the immune response. With the discovery of ipilumumab, an antibody directed against CTL4, scientists could now turn off the “off” switch, thereby turning on the immune system.

Survival advantages have been substantial. This therapy is now available to patients in need.

The second discovery represents a triumph for “targeted” therapy. As the gene BRAF, was recognized to be mutated in the majority of melanoma patients, drugs were developed to turn off this important pathway. Unfortunately, the first generation BRAF inhibitor sorafenib, could not shut down what proved to be the most common variant of the BRAF mutation, known as V600E.

To the rescue came a compound now known as vemurafenib. By turning off the V600E signal, those patients with this specific mutation (about 60 percent) responded dramatically.

While both these discoveries are meritorious, the responses in most patients unfortunately have not been very durable, with relapses generally occurring months or the first year after starting therapy. Interestingly, secondary pathways, like N-RAS and C-RAF, may step to the fore and overtake the effect of the BRAF inhibition. This offers hope that third generation small molecules will address these resistant clones.

In our laboratory, we are currently examining small molecules that inhibit the RAS and other pathways to determine whether new strategies may overcome these resistance mechanisms in melanoma. As a proof of concept, these reports from ASCO establish that the era of targeted therapy in melanoma is here.

Disrupting Cancer’s Circuitry – an Electrician’s View of Oncology

In many ways, cancer can be viewed like an integrated circuit. On-off switches and back up switches constitute the controls. When one of these switches stops working and a cell “short circuits,” cancer is the result. As we become more sophisticated in our understanding of cancer biology, we begin to create drugs that specifically target these short circuits.

On April 3, 2011, I will be reporting our most recent findings on novel compounds that target two parallel circuits in cancer cells. These compounds, or small molecules, disrupt the signal that drives cancer cell survival and proliferation. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still. The phenomenon of cross talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When we as therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what we have observed with these duel inhibitor combinations.

What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear. Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of our platform — for it allows us to explore drugs and combinations that most people wouldn’t think of. It is these counterintuitive explorations that will likely lead to meaningful advances.