Team science demands that alpha researchers work with other top dogs and share the investigation, the data and the credit. Baylin and Jones, leaders of SU2C’s epigenetics team, were rivals for years. “It does take an ego to do this business,” says Baylin, “because everybody is more than ready to tell you you’re wrong.” For these two, things have thawed so much that their families have vacationed together.
Haber, an oncologist, has similarly partnered with Massachusetts General biomedical engineer Mehmet Toner to lead an SU2C-backed team that has designed and built a smart chip device to trap circulating tumor cells (CTCs) in a blood sample. Many tumors release cells into the bloodstream; if a CTC finds purchase in another organ and starts to grow, that is metastasis. The breakaway cells are not easy to spot — there are a billion blood cells for every one of them — but detecting their presence is critical to stopping their spread.
The business-card-size detector the team built uses antibodies that bind to certain cell proteins to isolate and capture the CTCs. It’s possible the device will change the standard of care for treating several cancers, beginning with metastatic prostate cancer. The CTC chip’s role as a hunter-trapper is also being applied to lung cancer, where mutations can help direct powerful new therapies, to see how CTCs change and evolve during the course of treatment. With other cancers, like pancreatic cancer, where there are currently no mutations that can be targeted, CTCs are being analyzed to see if they can reveal new vulnerabilities in tumor cells.
Lassoing a single blood cell is complicated enough. But the pairing of bioengineers with oncologists was no small thing either, at least until they were thrown together by the SU2C grant. “The field had a bad rep and wasn’t moving forward,” says Haber, “but they learned DNA, and we learned equations.” His team even includes an entrepreneur-in-residence, Dr. Ravi Kapur, who was in charge of rolling out the prototype to the team’s collaborating institutions.
Big Pharma, Big Results
Cancer is a thief and biological con artist, breaking into and taking control of the mechanisms of a cell and coaxing it to grow and divide in dangerous ways. Cantley has spent a career chasing this cellular saboteur by, as he describes it, “teasing out signaling pathways” that govern not just growth but the very life span of a cell. If the malignant signaling can be silenced or reversed, the cancer won’t spread. In pursuit of that, he is now a co-leader of a team backed by SU2C that targets a pathway called PI3K, short for phosphoinositide 3-kinase. The pathway is a known driver in three women’s cancers: ovarian, endometrial and especially breast, which involves the PI3K mutation in 30% of cases. Says Cantley: “It’s the most frequently mutated oncogene in cancer.”
Drug companies have long been targeting mutations like this one to develop compounds that will interfere with the defective biochemical gateways. There are hundreds of drugs that may have some effect against some of the mutations, which sounds like an abundance of riches — but it’s also an abundance of complexity. That’s one reason that the pharma industry has a 95% failure rate for new products and that half of Phase III trials — the last step before approval — don’t cut it. “If I have 100 different drugs I can use in combination, then 100 times 100 is 10,000. You can’t do 10,000 trials,” says Sharp. But which ones can you do and should you do and on which patients? Since PI3K mutations are the most common type, those seemed like a perfect place to start for Cantley’s dream team, which is co-led by Dr. Gordon Mills of MD Anderson — another world-class PI3K pathway investigator — along with women’s-cancer specialists from Massachusetts General, Dana Farber (Harvard), Vanderbilt, Columbia University, Beth Israel Deaconess and Memorial Sloan-Kettering.
The goal is to launch trials as rapidly as the geneticists and biochemists solve the equation of matching mutations with drug compounds. In one of the best examples of the new model, Cantley, Dr. Gerburg Wulf and another researcher, José Baselga, proposed combining a PI3K inhibitor with a PARP inhibitor to combat a particularly pernicious mutation in the BRCA1 gene that results in high risk for developing ovarian cancer and a severe type of breast cancer known as triple-negative. PARP is the abbreviation for a group of enzymes that do repair work on damaged DNA strands — usually a good thing, unless the strands are producing cancer cells. Working on mouse models, the team got cures for BRCA1 mutant and triple-negative breast cancers when they combined a PI3K inhibitor and PARP inhibitor, which had never happened with other therapies.
Moving on to a human trial was also easier than it ordinarily is and illustrates what the new paradigm means for Big Pharma. The team needed a PI3K inhibitor from Novartis and a PARP inhibitor from AstraZeneca. Neither drug is approved for cancer treatment, and it’s rare to conduct a trial in which two unapproved drugs are combined. Because of concerns about intellectual property and other issues — no drugmaker wants to be smeared by the toxicity of another’s drug — companies are wary of collaboration. The success of the Cantley-Mills team had drug firms lining up. “Every company that had a PI3K inhibitor called me and asked would I work with them,” says Cantley. The result was almost without precedent: a human trial at five institutions with two unapproved drugs from two companies within about a year of discovery. “Four years ago if you said you were going to do that, you would have been laughed out of the room.”
The Big Targets
For all the progress made against some types of cancer, there are others that have never been anything but bad news. Take pancreatic cancer, an area that Sharp bluntly labels “a disaster.” The disease is often discovered in a late stage, and most tumors are inoperable. It has what researchers call bad biology — cancer cells that resist treatment. The goal of Von Hoff, who leads SU2C’s pancreatic dream team along with Dr. Craig Thompson, CEO of Memorial Sloan-Kettering, is to improve survival rates. Currently, less than 25% of patients with advanced pancreatic cancer make it to one year.