Internationally acclaimed oncology expert shares her insights on new targeted cancer therapies  

Renowned for her work in cancer research, Dr. Barbara Weber is a seasoned oncology leader with over 25 years of experience in cancer genetics and drug development. In this exclusive interview, she shares her unique involvement in cancer research and drug development and discusses Tango Therapeutics’ distinctive approach to developing targeted therapies.

Slone Partners: Dr. Weber, throughout your career you have made it your professional mission to advance the fight against cancer. Over the years, what has been your most fulfilling accomplishment towards this quest?

Dr. Weber: It is hard to pinpoint just one thing. I have been fortunate to be involved in work that went from basic laboratory beginnings to actual tangible patient benefit. For me, one of the most fulfilling accomplishments was the opportunity to personally interact with patients who directly benefitted from drugs I was involved with developing.

My academic career was largely focused on breast cancer genetics, studying people and families who inherited mutations in genes that put them at a very high risk of getting breast and ovarian cancer. Going from the fundamental genetic techniques to find the genes, to identifying families that had a gene mutation, to building the clinical programs that served those families was extremely rewarding.

We went from making linkage markers that helped us identify where the genes are in the genome, to sitting down with families who, for generations had been devastated by the loss of mothers, sisters, and aunts to breast and ovarian cancer without explanation. We were now able to tell them what was happening and what we could do to help them determine who in their family was at risk. We were able to provide them with strategies to reduce the likelihood that they would die from breast or ovarian cancer. To be able to understand what was going on and have a plan of action was an enormous blessing for them.

The second piece is when I moved from working in heritable genetics into thinking about how cancer genetics could change drug development. I was involved in the early stages of pushing for a different approach to clinical trials and drug development. We needed to stop doing drug discovery in the old way, which was broken down into 3 phases. Phase 1 was for dose finding and toxicity with no real expectation that the patients would benefit from the drug. Phase 1 was followed by multiple, big phase 2 studies that tried to get a sense of in which cancer types the drug might work. Phase 3 studies were large, expensive, randomized trials that would often fail. We started thinking about the patients who would most likely benefit from these drugs and how we should be selecting these patients from the very beginning. We needed to figure out who would benefit from each drug specifically and how to identify them for clinical trial enrollment. From the old development approach to the way we run trials now using biomarkers to select the patients most likely to respond, we were able to drive change, not only at GSK and Novartis, but for the entire industry. We began seeing responses and benefits in the very early stages of phase 1 with this new approach, shortening trials, benefitting more patients, making development less expensive and more likely to be successful.

Particularly at Novartis, I had the opportunity to directly interact with some of the patients who benefitted from this new approach, which was really amazing. The ALK inhibitor ceritinib was probably the most dramatic. We only accepted patients with an ALK translocation in their tumor from the very beginning of phase I, which was not at all standard at that time and generated a lot of debate in the company and with the study investigators. Some believed that approach would slow us down and was not the right thing to do. There were two very remarkable patients that benefitted from this approach directly. One was a 24-year old college student dying of lung cancer with an ALK translocation who had a dramatic response to ceritinib and was able to return to school. Another was a poet from New Zealand who was diagnosed with lung cancer with an ALK translocation while she was pregnant with her 3^rd child. Her response to ceritinib lasted for almost 4 years.

Being a part of these families’ journeys during that time was really remarkable.

Slone Partners: Could you explain the concept of synthetic lethality and how it is different from other targeted therapies?

Dr. Weber: Synthetic lethality is a concept that was discovered in fruit flies long before people knew what DNA was. Looking under a microscope, fruit flies with a range of visible defects in their eyes, or wings or bodies were described. What geneticists then discovered was that fruit flies could have one of these defects, but when mated with a fruit fly with a different defect, offspring was not viable. This was evidence that fruit flies could tolerate one mutation or the other, but they could not tolerate both. This illustrates the concept of synthetic lethality. Synthetic lethality occurs when two defects combined are lethal when neither would be lethal by themselves.

In cancer cells, the same thing happens when you start with a specific gene mutation and identify a second gene that is required for those cells to survive. For example, a drug that inhibits a protein required for P53-mutant cells to survive will kill only the cancer cells with that mutation and not normal cells. It is a vulnerability (synthetic lethality) that happens in cancer cells because of an existing mutation that we can take advantage of to identify new drug targets.

It is very valuable in cancer treatment because the presence of the first gene mutation of a synthetic lethal pair has no impact on cell viability, in fact may help cancer cells survive, but inhibiting the gene product of the other half of a synthetic lethal pair, results in cancer cell death without affecting normal, non-mutant cells. In other words, it only kills the cancer cells since normal cells only see the drug; they do not have the pre-existing mutation that makes cells vulnerable to the drug. Hence, drugging synthetic pairs can be very active against cancer with very little effect against normal cells, which markedly reduces toxicity.

Slone Partners: How do you see synthetic lethality, with regards to cancer therapy, in the next 3 to 5 years?

Dr. Weber: I believe that synthetic lethality-based target discovery is opening a door to the next big wave of new cancer targets and advances for patients, since almost all cancers have tumor-suppressor gene mutations. You may have heard this analogy before: Oncogenes are considered “gas pedal” mutations, whereas tumor-suppressor genes are “brake” mutations. In other words, an activated oncogene is driving the cell to grow faster and act like a cancer cell, mutations into a cancer suppressor gene are loss-of-function mutations that remove normal brakes on cell growth. We cannot target something that is lost, consequently we do not have the ability to target any tumor-suppressor gene mutations in cancer, even though we have known what they were for years. Finding synthetic lethal partners for these tumor-suppressor gene mutations is the only way I know of at present to do it.

Slone Partners: Do you see these Synthetic Lethal drugs being available in the clinic in the next 3 to 5 years? What are some limitations you are seeing at this stage?

Dr. Weber: I do. The first one, which is the BRCA1-2 PARP interaction, discovered by one of our Founders, Alan Ashworth, is now well into the clinic and the results are amazing. Ovarian cancer patients with BRCA1 or BRCA2 mutations on a PARP inhibitor after chemotherapy, have a median progression free survival approaching two years (median PFS) compared to approximately 6 months without a PARP inhibitor, providing clinical proof-of-concept. At Tango Therapeutics, we have identified a number of novel drug targets already in the first 6 months since our launch. It will take us several years to make drugs against those targets and take them into the clinic, but within the next 5 years, I believe there will be multiple synthetic lethal drugs in the clinic.

Slone Partners: How does Tango Therapeutics develop these new therapies and determine patient selection to smooth the transition into the clinical stage?

Dr. Weber: Existing data support the idea that almost all synthetic lethal pairs are context-dependent. This means that a P53 synthetic lethal pair in lung cancer might not be the same as P53 synthetic lethal pair in liver cancer. We are doing drug discovery in models that mimic the cancer genetics of patients we want to be able to treat. We start with unmet medical need – cancer types that do not currently have the effective targeted therapies or respond well to immunotherapies, and may not respond well to chemotherapy. Then, we identify the tumor-suppressor genes lost in those models and identify a synthetic lethal partner for that tumor-suppressor gene in that tumor type. At Tango, because we do target discovery in models that mimic the patients we want to treat, thus once we make the drugs we know exactly what the patient selection markers are and how to select those patients for the trial.

Slone Partners: What do you see as the biggest roadblock in cancer research today, and what can we do to change it?

Dr. Weber: The biggest roadblock in cancer research is still making good molecules. Medicinal chemistry, getting from a target to a drug that you can give to patients, is hard. I see a path forward to discovering a lot of good targets, but can we turn these targets into really effective drugs that we can give safely to patients? Sometimes, we will succeed and sometimes we will not. 

About Barbara Weber, MD

Chief Executive Officer, Tango Therapeutics
Venture Partner, Third Rock Ventures

Barbara Weber joined Third Rock Ventures in 2015 to focus on oncology research and development opportunities throughout the portfolio. In that role, she served as the interim CMO for Neon Therapeutics from launch in 2015 until Sept 2017, when a permanent Head of R & D was recruited. She also played a leadership role in creating Relay Therapeutics, launched in March 2016. However, her passion was always for a cancer therapeutics company to take full advantage of recent advances in cancer genetics to take the next big step forward for patients.

That company is Tango Therapeutics. Tango started as an idea at Third Rock in 2015 and moved to public launch with a $55M Series A from TRV in March 2017, with Barbara as the interim CEO and 6 full-time employees. In September 2017, Barbara accepted the position as the permanent, full time CEO of Tango, and leads a team of 20 experienced cancer geneticists and drug developers supported by the exceptional company builders at Third Rock and Board of Directors that strongly support the mission. Tango has a fully-operational target discovery platform, two full drug discovery programs and a score of targets to bring forward that will make a substantial difference to patients. Prior to joining Third Rock, Barbara held the position of Senior Vice President and Global Head of Oncology Translational Medicine at Novartis from 2009 to 2015. Prior to joining Novartis, Barbara served as Vice President Oncology Discovery and Translational Medicine at GlaxoSmithKline from 2005 to 2009. Until 2005, Barbara was a Professor of Medicine and Genetics at The University of Pennsylvania School of Medicine, leading a clinical and translational research program in cancer genetics and the UPenn Cancer Center Breast Cancer program.

Barbara is a member of the honorary societies American Association of Physicians and the American Society for Clinical Investigation, of which she served as President in 2005. Barbara also has served on numerous scientific advisory boards and on the Board of Directors of both the American Society of Clinical Oncology and the American Association of Cancer Research. Barbara is a graduate of the University of Washington School of Medicine. She completed her residency in Internal Medicine at Yale University School of Medicine and her fellowship in Medical Oncology at the Dana-Farber Cancer Institute.

Read our exclusive interview with Dr. Michael Sherman, CMO and SVP of Health Services at Harvard Pilgrim Healthcare.