Future (Cancer) Shock

Two related clinical trials were reported in the last several months describing the use of heat shock protein 90 (HSP90) inhibitors in lung cancer. Both trials fell short of their pre-specified endpoints casting a pall upon these drugs. However, the study of HSP90 inhibitors should not be abandoned based on these finding, as this is a fertile area of investigation and offers opportunities for the future.

Human cells marshal many defenses against stress. Thermal injury can damage basic cellular functions by denaturing (inactivating) proteins. The machinery of cells is largely comprised of protein enzymes. Excessive heat coagulates proteins much the way the albumin of an egg turns white during cooking. The loss of fluidity and function ultimately results in cell death. The heat shock proteins come to the rescue by shepherding these proteins away from injury and protecting them from denaturation.

220px-Hsp90There are many different heat shock proteins found in human cells, but one of the most abundant and active in cancer cells is known as HSP90 for its molecular weight in the range of 90-kilodaltons. Over the last two decades investigators have explored the use of small molecules to inhibit these important proteins. Among the first compounds to be isolated and applied were derivatives of geldenamycin. Although geldenamycin itself is a poison that causes severe liver damage, its derivative 17-AAG, also known as tanespimycin, has successfully entered clinical trials.

The current studies examined two other HSP90 inhibitors. One retaspimycin, has been developed by Infinity Pharmaceuticals. This clinical trial combined retaspimycin with docetaxel and compared results with docetaxel alone in 226 patients with recurrent lung cancer. None of the patients had received docetaxel prior to the trial. Drugs were administered every three weeks and the efficacy endpoint was survival with a subset analysis focused on those with squamous cell cancer. The trial fell short of its pre-designated endpoint. Interestingly, the study failed to provide benefit even in patients who were specifically targeted by their tumor’s expression of the K-Ras, p53 or by elevated blood levels of HSP90, the putative biomarkers for response.

The second trial examined a different HSP90 inhibitor developed by Synta Pharmaceuticals. The drug ganetespib was combined with docetaxel and the combination was compared with docetaxel alone. The results just reported indicate that the combination provided a median survival of 10.7 months, while docetaxel alone provided a median survival of 7.4 month. Although this represented a three month improvement, it did not meet the pre-specified target.

Taken together, these results could dampen enthusiasm for these agents. This would be unfortunate, for this class of drugs is active in a number of human tumors. We observed favorable activity and synergy for the HSP90 inhibitor geldenamycin and its derivative 17-AAG as we reported (Nagourney RA et al Proc. AACR, 2005). More importantly, 17-AAG (tanespimycin) provided objective responses in 22% and clinical benefit in 59% of patients with recurrent HER2 positive breast cancer after these patients had failed therapy with Herceptin. This clearly supports the role of HSP90 inhibition in breast cancer and would suggest that other more carefully selected target diseases could benefit as well.

The function of HSP90 is not completely understood as it influences the intracellular trafficking of dozens ofHsp90cycle proteins. One of the complexities of this class of drugs is that they protect and enhance the function of both good and bad proteins. After all, the HSP90 protein doesn’t know which proteins we, as cancer doctors, would like it to protect.

When we apply the EVA-PCD analysis to these and related classes of compounds we focus our attention upon the downstream effects, namely the loss of cell survival. That is, whatever proteins are influenced, the important question remains “did that effect cause the cells to die?” Classes of compounds with nonspecific targets like the HSP90 inhibitors will surely be the most difficult to characterize at a genomic or proteomic level: What protein? What gene?

Functional platforms like the EVA-PCD offer unique opportunities to study these classes of agents. We are convinced that the HSP90 inhibitors have a role in cancer therapy. It would be unfortunate if these setbacks led us to “throw the baby out with the (hot) bathwater,” thus slowing or preventing their use in cancer treatment.

A Tribute to Loretta Stamos 1939 – 2014

RAN & Loretta cropped lo res

Dr. Nagourney and Loretta Stamos

On Monday, September 22, 2014, we lost a great ally and a better friend.

Loretta Stamos lost her own fight with cancer, the very disease that she had worked so tirelessly to defeat. I first met Loretta in 1995 when her brother Jake was diagnosed with advanced lung cancer. His physicians didn’t offer much hope. At our meeting, I explained my approach to cancer therapy using each patient’s cells to select drugs (EVA-PCD functional profile).

“Let’s do it,” said Loretta.

“Now?” I asked.

“Why not?” she replied. As I would come to know over our 20 year friendship, Loretta didn’t mince words and was not one to take no for an answer.

A simple two drug combination was recommended for Jake, but his physicians declined. Loretta asked if I would assume his care. As I was out-of-network for his HMO, each time we treated her brother, Loretta generously covered the chemotherapy costs. After two cycles of treatment, the pleural fluid stopped accumulating. Jake gained weight and returned to some of his normal activities.

The in-network physicians began to realize that they were on the wrong side of this equation and suddenly offered to continue the treatments at their facility. Jake’s cancer ultimately progressed. His extensive metastatic disease involving his lung and bones was too aggressive for even the best chemotherapy to cure. Despite the sad loss, we had succeeded in showing that every patient deserved the chance to get better regardless of their insurance or finances.

Loretta wondered what would have happened if she had not been there to help. I explainRAN_LS_JS2 lo resed that the laboratory analyses were too costly for me to donate. Though they came in at a fraction of the price of a single dose of chemotherapy, many insurers refused to cover them. Loretta said, “I’m going to make sure that people who need these tests will never be denied.” And the Vanguard Cancer Foundation (VCF) was born.

Months of work, committee meetings and planning sessions culminated in a “A Night in Brazil,” a gala benefit that raised $100,000. John Stamos, Dave Coulier and Bob Saget turned in stellar performances as the MCs and a great time was had by all. More importantly, for the first time we could to say to patients, “We can find the treatment that’s right for you and if you can’t afford it, we’ll give it to you.” With each passing year the fund grew as did the number of patients we could help.

John and Loretta Stamos w-Sarah AmentoWhat a luxury to never turn a patient away. What an opportunity to help uninsured and younger patients. What a pleasure to see the good responses, even in some patients considered previously “untreatable.” I was overwhelmed by Loretta’s dedication and the kindness that she and the VCF members showed to patients in need. Every year we would recognize Loretta and her family for their hard work and generous contributions, and every year Loretta would say that she did this because “I made her brother smile.”

There is a silver lining to even the darkest cloud. It was Loretta who put it most poignantly when she defined the mission of the Vanguard Cancer Foundation as providing lifesaving care to “persons of worth but not of means.” The most fitting tribute of all for this noble soul is the more than 400 patients who can thank Loretta Stamos for a second chance at life.