March 2011

Drug discovery: major challenges

Photo credit: Dąbrowa Górnicza

Last year, in the United States, more than 1.5 million new cancer cases were identified, with lung, prostate and breast cancer at the top of the list. Cancer was the cause of more than 500,000 deaths, 28 percent due to lung cancer. According to a report from the American Society of Clinical Oncology titled “Clinical Cancer Advances 2010: Annual Report on Progress Against Cancer,” “Death rates dropped 1.6 percent annually from 2001 to 2006, mainly due to reductions in new cases and death rates for the three most common cancers in men (lung, prostate and colorectal cancers) and for two of the three leading cancers in women (breast and colorectal cancer).”

The report is very informative for basic scientists and clinicians alike and leaves the reader with the impression that major breakthroughs are happening every day. For example, “a randomized, phase III drug trial in patients with metastatic pancreatic cancer was the first to demonstrate a significant survival improvement in individuals with stage IV adenocarcinoma of the pancreas … treatment with FOLFIRINOX – a combination of the chemotherapy drugs 5-fluorouracil, leucovorin, irinotecan and oxaliplatin – resulted in better response rates, progression-free survival and overall survival compared to standard single-drug treatment with gemcitabine (Gemzar).

“A phase III trial found that adding the anti-angiogenesis drug bevacizumab [Avastin, Genentech/Roche] – which targets tumor blood vessel growth and development – to the standard chemotherapy drug combination carboplatin and paclitaxel helped women with advanced ovarian cancers live significantly longer without their disease progressing than chemotherapy alone.”

A dramatic discovery involved a BRAF inhibitor for advanced melanoma: “Researchers showed that the majority of advanced melanoma patients with a specific BRAF gene mutation (V600E mutant BRAF) responded to a new BRAF inhibitor, PLX4032 (Roche). In the second part of a phase I trial, tumors either completely or partially regressed, including metastases in the bone and liver, in 81 percent of patients.”

However, nowhere in the report did the authors mention the fact that these targeted, molecular therapies did relatively little to prolong survival. The FOLFIRINOX study reported a 6.4 versus 3.3 month progression-free survival for metastatic pancreatic cancer; women who took Avastin during standard chemotherapy for ovarian cancer lived about four months longer. And frustratingly, many of the most dramatically responsive BRAF patients relapsed within a year.

More encouraging are the data for ipilimumab, a monoclonal anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody that Bristol Myers Squibb is testing as a treatment for metastatic melanoma and other cancers, including prostate and lung cancers. Ipilimumab blocks the inhibitory signal of CTLA-4, thereby sustaining an active immune attack on cancer cells. In a Phase III trial, about 45 percent of patients treated with ipilimumab were alive at one year compared with 25 percent of patients in the control arm. At two years, 22 to 24 percent of patients treated with ipilimumab were alive compared with 14 percent of patients in the control arm. This is the first therapy ever to show a survival benefit for metastatic melanoma in a randomized clinical trial; it currently is under priority review by the U.S. Food and Drug Administration. If ipilimumab is approved for the treatment of melanoma, physicians will be at liberty to prescribe this drug off-label for the treatment of other appropriate conditions, possibly including prostate and lung cancer.

Do these data make us feel encouraged or discouraged? To be fair, these studies targeted the most aggressive cancers possible. Clearly more work is needed; the cures are not yet in hand. An added challenge is the fact that the pharmaceutical industry estimates that it costs more than $800 million to bring a single drug to market if one includes the cost of products that fail along the way (and most do). Although some have criticized this estimate as difficult to verify, no one disputes the high costs of years of drug development and animal studies followed by the clinical trials and testing required for FDA approval. For each exciting new agent, combination trials also will be needed, and one can imagine a number of combinations and additional indications that deserve further study. If only it were easier (and cheaper).

In addition to industry-funded trials, more than 25,000 patients participate in the National Cancer Institute’s clinical trials annually. Following a careful review by the Institute of Medicine, the NCI currently is working hard to improve the speed and efficiency of the design, launch and conduct of clinical trials, hoping to incorporate innovative science and trial design into cancer trials, improve prioritization, selection, support and completion of clinical trials, and incentivize the participation of patients and physicians. Given an annual clinical trial investment of more than $800 million, these goals will be important for NCI to achieve.

Beyond cancer, the goals of the National Institutes of Health Clinical and Translational Science Awards program are to speed the translation of laboratory discoveries into treatments for patients, to engage communities in clinical research efforts, and to train a new generation of clinical and translational researchers. This consortium includes 55 medical research institutions located throughout the U.S. The CTSA consortium presently is funded by the NIH National Center for Research Resources.

Recently, NIH Director Francis Collins proposed the creation of a new National Center for Advancing Translational Sciences that would oversee the CTSA program. According to available information, “NCATS is not intended to be a drug company. It is a facilitator of translational research across the NIH and complementary to translational research already being conducted and supported on a large scale in the individual NIH Institutes and Centers. NCATS will seek ways to leverage science to bring new ideas and materials to the attention of industry by demonstrating their value.” In principle, it makes sense to house the CTSA program in an organizational unit that will do everything possible to facilitate drug discovery.

The creation of NCATS also has raised concerns, however, in part because it will disband the National Center for Research Resources that oversees critical, long-term technology development. NCRR supports the development of new technologies, including instrumentation, software and methods for biomedical research through a constellation of programs including Biomedical Technology Research Centers. NCRR also supports Shared Instrumentation and High-End Instrumentation Grant Programs. Currently under discussion is where to house these programs; the American Society for Biochemistry and Molecular Biology wants to be sure that they continue to be well nurtured, as they support critical, cutting-edge mass spectrometry, synchrotron X-ray technologies, molecular dynamics computation, optical and laser technology, and fluorescence spectroscopy.

All of us want cures for a long list of debilitating illnesses, and we hope that NCATS will focus on what NIH does best. Basic research is essential for disease target identification, such as BRAF in melanoma. When patients relapse, basic science also will be required to explain the molecular basis for therapeutic resistance and drug-target bypass. At the same time, the pharmaceutical industry has invested billions of dollars in drug screening and medicinal chemistry, and they are experts in drug design. It makes obvious sense to try to leverage all the expertise that industry can provide. In cancer, NCATS can encourage innovation in clinical trials and promote both industrial and industry-academic collaborations. Combination therapies are going to be essential given the recalcitrance of tumors to targeted intervention, and collaboration will be important in this regard. The U.S. Food and Drug Administration also will be an important partner as combination regimens are evaluated differently, and revisiting those guidelines may benefit all of us.

ASBMB President Suzanne Pfeffer ( is a biochemistry professor at the Stanford University School of Medicine.

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