February 3, 2010
By Jeffrey Norris
Before coming to UCSF, Chancellor Susan Desmond-Hellmann, MD, MPH, was a practicing oncologist, and later she was president of product development at Genentech, where she took the lead in developing some of the most successful cancer-fighting drugs in history.
UCSF Chancellor Susan Desmond-Hellmann delivers the keynote address at the UCSF Helen Diller Family Comprehensive Cancer Center’s Breast Oncology Program on Jan. 28.
Among these drugs are Avastin, Rituxan, Tarceva and Herceptin, the last of which was the first anti-cancer treatment tailored to target a molecule that is abnormally produced in a difficult-to-treat subset of breast cancers.
Given her background, it’s no surprise that Desmond-Hellmann was asked to deliver the keynote address at this year’s annual symposium for the UCSF Helen Diller Family Comprehensive Cancer Center’s Breast Oncology Program Scientific Retreat last week. Watch the address on YouTube.
The theme of her talk was the need for smarter drug development that harnesses all available information on clinical outcomes, genetics, tumor biology and early “surrogate” signs of positive responses to treatment to identify the most promising drugs and move them through the pipeline more quickly to meet the needs of cancer patients.
Golden Age of Drug Development
During her talk, Desmond-Hellmann referred to the years from 1997 to 2001 as the golden years. It was then that the drugs Rituxan, Herceptin and Gleevec became widely available for treatment, with each having a great impact on patient survival and in changing the ways that researchers and physicians think about cancer. UCSF can play an important role in initiating a new golden age of drug development, Desmond-Hellmann says.
Rituxan, the first monoclonal antibody approved for treatment of a human cancer — non-Hodgkins lymphoma — was special because of its rapid approval and launch, Desmond-Hellmann says. “The pivotal trial for Rituxan had 166 patients. … It was uncontrolled, because the standard therapy for non-Hodgkin’s lymphoma at the time was to watch-and-wait, to avoid the complications of not-effective-enough chemotherapy.
“The cure rate significantly increased,” Desmond-Hellmann says. “And one of the most interesting aspects that’s still under study, is this possibility of turning cancer into a chronic disease,” in the same way that HIV infection is regarded as a chronic but not necessarily rapidly fatal condition.
Herceptin is a type of personalized medicine aimed at a protein called Her2 that is abnormal in a subset of breast cancers. Its presence is associated with a worse prognosis.
“The rapid FDA approval was due to a large unmet need and to patient advocate demands,” Desmond-Hellman says.
“Before [Herceptin] there was no treatment option specific to Her2-positive breast cancer, and it was a rapid death sentence for most women. … After, there was about a 20 percent difference in disease-free survival at five years, and the new therapy reduced the chance of cancer returning by 52 percent.
“Gleevec was the perfect storm of discovery, advocacy and commitment,” Desmond-Hellmann says, “with a fast FDA approval and a phenomenal success rate in treating chronic myelogenous leukemia (CML). Before Gleevec only 30 percent of patients with CML survived five years after diagnosis and treatments have serious side effects.” Now there is a complete hematological response in more than 98 percent of patients and a 90 percent five-year survival rate, she says.
“These are the kinds of outcomes we should strive for in hematology-oncology,” Desmond-Hellmann says.
So why are we no longer witness to golden years for the development of cancer-fighting drugs?
UCSF Chancellor Susan Desmond-Hellmann, center, talks with molecular biologist Laura van ‘t Veer and Frank McCormick, director of the UCSF Helen Diller Family Comprehensive Cancer Center.
“Cancer research is too slow, too expensive, too inefficient and too uncertain,” Desmond-Hellmann says. She used another Genentech drug as an example of slow translation of discovery into clinical practice. The concept of blocking a tumor’s blood vessel supply by targeting proteins responsible for new blood vessel growth was first described in 1971. However, the first drug to work in part by this mechanism, called Avastin, was not tested in clinical trials until 1997, marking 26 years from concept to first trials in humans. The drugs were finally approved for sale by the FDA in 2004.
Desmond-Hellmann mentioned four examples of treatments as holding as much promise as the drugs of the golden years. They are targeted at different molecules and biochemical pathways. Certain types of cancer depend on the biochemical activities of these targeted molecules for their survival.
One category includes drugs that inhibit the action of a protein called BRAF. BRAF drives as many as 60 percent of malignant melanomas, and eight percent of solid tumors, Desmond-Hellmann says.
Another group of promising drugs in development targets the “hedgehog” biochemical pathway in basal cell carcinoma, a type of skin cancer, and in some forms of medulloblastoma, a deadly brain cancer.
About five percent of patients with lung cancers may greatly benefit from drugs that target a protein called ALK.
The last group of promising drugs mentioned by Desmond-Hellmann inhibits the action of the protein called PARP. These show promise in treating the most difficult-to-treat “triple negative” breast cancers, which lack three more common markers found in many breast cancers.
To help make drug development faster, cheaper and more predictable, Desmond-Hellmann says, “We need to understand earlier and with greater confidence what the best ideas are.”
“I think we should be extremely dogged — even if it’s for a narrow group of patients — to uncover those cancers driven primarily by a single [biochemical] pathway.” Disrupting such an important lifeline for these cancers could have a great impact on patient survival.
To explore the potential of combination therapies, Desmond-Hellmann says, “We need to understand how to test more than one product at a time and to do it efficiently, in a way that gives us clear signals.”
Desmond-Hellmann cited the need for better early markers of success or failure in clinical trials. “I think survival is the best outcome measure, but if survival is extended, I am not willing to wait beyond our lifetimes to know the answer, and more importantly patients should not have to wait.”
What is learned in clinical trials or even after drug approval can be used to guide future research, Desmond-Hellmann says. “There is no reason in today’s world, with electronic medical records and information technology that we shouldn’t know what happens with every patient. We need both outcomes and molecular correlates on every cancer patient. … There is so much information on safety, efficacy, potential good and potential harm, and we need to have that.”
Desmond-Hellmann notes that affordability and patient access to the best treatments are important issues. “We need to make sure that the right product reaches the right patient at the right time and that the patient has access to it.”
For each cancer patient, the goal is to be able to say, “Here’s the kind of cancer you have, and in fact, we have something for that.” UCSF has an unprecedented opportunity and great talent to contribute to accomplishing this goal, Desmond-Hellmann says.
Advancing Ideas More Quickly
In an interview after her keynote address, Desmond-Hellmann elaborated on points she made during her presentation and discussed ways in which academic researchers can work with industry and patient-advocate groups to advance promising treatment ideas more quickly.
Medical oncologist Hope Rugo talks with UCSF Chancellor Susan Desmond-Hellmann while Thea Tlsty, professor of pathology, looks on.
Desmond-Hellmann says that a drug’s transition from experimental to well-understood is more gradual than what is suggested by the division between experimental and FDA-approved drugs. The tag “approved” has the “sense that we know everything about it,” even for newly approved drugs, she says. Desmond-Hellmann envisions a category of new drugs that could be used in a somewhat restricted way, and which could not be advertised directly to patients. “It’s important to communicate the uncertainty and to dampen down the marketing instinct,” she says.
When it comes to UC-industry collaborations, especially those involving patient studies, Desmond-Hellmann says, “I think we could all do a better job of understanding what everyone’s objectives are.
“We should focus on our shared goals, but also to really be clear about where we have differences. Talk out loud about where you are going to disagree and how you are going to manage communication of results, confidentiality, publication … and how to involve patients.
“People worry that too often when the UC system looks at interactions with industry, it’s a lot about what you can’t do, and what’s not possible. Great investigators at UCSF who really want to change medicine, change science and make an impact would like to work with people who say, ‘You want to cure cancer; you want to change the world. How are we going to get that done?’ When you’re in administration, or legal, or tech transfer and have that attitude, it makes a huge difference.”
Desmond-Hellmann cited innovative clinical trials led by UCSF breast oncologist Laura Esserman, MD, and colleagues as a successful attempt to break through traditional ways of organizing and carrying out research.
“These are precedent-setting trials, and it takes the kind of relentless pursuit of better treatments for patients to say, ‘okay no one has ever done this before. Well, how do you do it? Why can’t we do it? What’s possible?
“People sign up for that. It’s so inspiring and so thrilling when you’re participating in that. …The no-can-do attitude comes from a lack of involvement and a lack of inclusion. … That’s one of the reasons I’m interested in collaborative science and team science.”
Photos by Elisabeth Fall/fallfoto.com