When the Drugs Stop Working

Some patients respond to PLX4032, then develop resistance to it. What are Mass General scientists doing to reverse that phenomenon?The initial results in the targeted therapy studies are striking, and for doctor and patient hold out so much hope.The patients with life-threatening Stage IV metastatic melanoma are given PLX4032, the best known of a family of experimental drugs called B-RAF inhibitors. A stunning 90 percent of the patients — who have been selected to participate in the studies because their tumor cells have a mutation of the B-RAF gene — are witnessing their tumors shrink. Within approximately two months their tumors, both visible and invisible, have shrunk to an average of 20 percent their initial size, and stay that way for months afterward. Symptoms fade. Lives become more normal.

By 10 months after the beginning of treatment, however, half the patients have begun to relapse. In the months that follow, the vast majority does so as well. The patients have been given extra months to live, but the now drug-resistant tumors start growing again as the cancer resumes its relentless, lethal march.

But thanks to groundbreaking research and an array of clinical trials being conducted at Massachusetts General Hospital and elsewhere, the bright promise of targeted therapy is not diminished by these tragic setbacks.

Dr. David Fisher, director of the Melanoma Program at the Mass General Cancer Center and chief of the MGH Department of Dermatology, and a team of researchers from a broad range of disciplines have already begun to understand how tumors are evading the BRAF inhibitors and are already zeroing in on additional therapies to prolong patients’ lives.

Dr. Fisher, who has conducted research into melanoma for 15 years, and has focused on the performance of BRAF inhibitors in recent years, appears not in the least dismayed by the limits of the targeted therapy so far. Drug resistance, he says, is a common challenge that has been overcome by cancer researchers in the past, and targeted therapy represents “the most striking explosion” in the search for treatment of advanced stage melanoma.

“It’s very uncommon in oncology that a (new) drug that works will cure people,” he says. “If you look at Hodgkin’s Disease or the curable cancers including testicular cancer, historically the first evidence that the right drugs were being used was that patients with very advanced disease started to have shrinkages that lasted for a while and then the tumors would start to grow again.  Then researchers started combining the drug with other drugs or changed the dose and eventually the patients (who?) would get bigger and bigger responses, longer and longer duration of response and eventually—boom there was a real cure.  So this is, in fact, a very exciting moment in the melanoma field because suddenly we find ourselves in the same terrain of trying to build on these results that in other tumors ended up working.”

The options Mass General researchers are considering for further therapy are guided by an understanding of the cellular chain of events leading to runaway growth in the tumors. Within healthy cells there are biochemical signaling pathways in which a sequence of proteins called kinases signal one after another to govern cell functions. The MAPK/ERK signaling pathway that is the focus of this research governs cell division and reproduction. In the melanomas being treated in these studies, the B-RAF gene, which activates the braf protein, a key kinase in the MAPK/ERK signaling pathway, is mutated and stuck in the “on” position, sending out a constant signal to spur cell growth.

Keith Flaherty, MD, director of Developmental Therapeutics at the MGH Cancer Center and the chief designer of the BRAF inhibitor multi-center clinical trials, says that close scrutiny of patients’ tumors shows that BRAF inhibitors successfully block about 99 percent of the MAPK pathway, and continue to block the BRAF signal even after the tumors resume their growth.  According to Drs. Fisher and Flaherty, that means two important things: first,  that the BRAF inhibitors don’t stop working, but, second, that the melanoma cells have “figured out” a way around that obstacle.

Dr. Fisher and his colleagues are also confronting two phases of drug resistance. In primary resistance, the melanoma tumors have built into them alternate signaling pathways, which is what allows the 20 percent of the tumor mass to survive the BRAF inhibitors. Secondary resistance refers to new growth mechanisms that develop in the tumor, the results of which are observed at the point of renewed tumor growth.

A passionate proponent of targeted therapy among clinical oncologists, Dr. Flaherty points to two main avenues of advancement to build on the success of B-RAF inhibitors: finding ways to build supplemental “roadblocks” on the signaling pathways that have already been impaired, and using another brand-new type of immune therapy to make the tumor cells more visible to the body’s own defenses.

He points to a number of ideas for additional roadblocks that have been researched and are or will be tested in human trials. Evidence has emerged recently, he says, that the melanomas, through an as-yet-unknown process, have managed to reopen the MAPK pathway by activating CRAF, a close cousin of BRAF that is not mutated and which acts on the next kinase in the series, called MEK. Drug companies have already produced both CRAF and MEK inhibitors, and both will be administered to patients in combination with BRAF inhibitors. And there are even signs in the laboratory, he says, that blocking the next kinase in the sequence after MEK, ERK, holds promise as well. The goal of this entire approach, he says, is to impact both primary and secondary resistance: to block more of the pathway from the start, leading to a greater initial reduction in the size of tumors, and dramatically forestall and slow the regrowth of the tumor.

The area of immune therapy also offers multiple avenues of advancement. Flaherty says the next generation of targeted therapies, for example, will seek to restore tumor suppression genes, which allow the body to detect genetic damage in cells and prevent the onset of cancer.  In the meantime, immune therapy initiatives are evolving from attempts to stimulate the immune system to be more active, which are more prone to negative side-effects, to helping the immune system recognize malignant cells that have learned to hide from the body’s natural defenses.

A preclinical trial at Mass General, for example, has prompted researchers to plan to administer BRAF inhibitors along with the latest immunotherapies, according to research published  in June for the journal Cancer Research, authored by MGH investigator Jennifer A. Wargo, MD. , Dr. Wargo, a surgical oncologist and melanoma researcher at the MGH Cancer Center, found that unlike other MAPK pathway inhibitors, BRAF inhibitors greatly restore melanoma cells’ visibility to the immune system without impairing function of the vital T cells.

Dr. Flaherty, who has been closely monitoring recipients of PLX4032 since the beginning of Phase I trials, says 20 percent of patients still have not relapsed 18 months after beginning treatment, and it is not yet clear when they will. He says cautiously that he believes researchers are four to five years away from extending survival times to several years for patients with the BRAF mutation.

In the coming year, he says, a new grant will be sought that will bring together lab investigators and clinical investigators to deal with research into both primary and secondary resistance. Stopping primary resistance represents a cure. Responding to secondary resistance is disease control.

“We’ll take disease control for now,” he says. “Metastatic melanoma is a horrendous cancer. So we’ll continue to look into the process of stopping the cancer’s work-arounds, but we have to keep a steady eye on how to make it more complete.”