A targeted therapy against pancreatic cancer

Place: conference room, IMDEA Nanociencia.

Abstract:

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest survival rates in the Western World. These high levels of mortality are mainly attributed to late diagnosis and the lack of efficacious treatments. Indeed, current therapeutic options still rely on old cytotoxic drugs such FOLFIRINOX, Gemcitabine or Nab-Paclitaxel. This situation is paradoxical considering the significant progress made during the last two decades in understanding PDAC biology, mainly thanks to the development of genetically engineered mouse models that faithfully reproduce the natural history of the human disease. It is well established that more than 90% of all PDACs are initiated by KRAS mutations follow by inactivation of well characterized tumors suppressors such as P53, P16/P19 or Smad4. Although human KRAS oncogenes were first identified in 1982, for over three decades KRAS oncoproteins were thought to be undruggable. Following the identification in 2013 of a small groove in the KRASG12C oncoprotein that led to the generation of sotorasib, the first KRAS inhibitor approved by the FDA, there has been a frantic race to develop new KRAS inhibitors either selective against other isoforms or panKRAS and panRAS(ON) inhibitors of wider spectrum.

Unfortunately, KRAS inhibitors have, so far, provided limited benefits due to rapid onset of tumor resistance. Hence their future will require the development of combination therapies not only to increase their anti-tumor effects but to avoid tumor resistance. Within these lines, we reasoned that instead of targeting KRAS itself, it might be more efficacious to target its signaling pathways at independent nodes. Subsequent studies with genetically engineered mouse tumor revealed a therapeutic strategy that combined inhibition of three independent signalling nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS pathways. Genetic elimination of these independent nodes in orthotopic mouse tumor models resulted in their complete and durable regression, leading to tumor-free mice for 300 days.  Importantly, this triple targeting strategy did not induce significant toxicities. Next, we validated this therapeutic strategy using pharmacological approaches. To replace RAF1 ablation, due to the lack of suitable RAF1 inhibitors, we decided to target KRAS by using the RAS(ON) inhibitor RMC-6236. To replace EGFR ablation we decided to use the Pan-ERBB kinase inhibitor Afatinib and to replace STAT3 elimination we used a selective STAT3 degrader SD36. Exposure of orthotopic mouse pancreatic tumors to the triple therapy, RMC-6236, Afatinib and SD36 faithfully reproduced the results obtained using genetic ablation approaches. That is, all treated tumor regressed completely without developing any signs of tumor resistance for at least 250 days. Analysis of their pancreas at the end of the experiment failed to reveal signs of tumor tissue or even of desmoplastic stroma. More recently, we have extended these results to genetically engineered tumor models obtaining very similar results.

Finally, we have also validated this therapeutic strategy in tumors derived from cancer patients (PDX). Six independent human pancreatic tumors were implanted in three mice each. Out of the 18 implanted animals, 16 completely regressed without signs of tumor resistance, even though due to the nature of the recipient immunocompromised animals, we were only able to maintain them for 80 days post treatment. Of importance, this triple therapy was well tolerated by all the animals. These results should open the door to the design of clinical trials that might help pancreatic cancer patients in a forthcoming future.

Short biography:

Mariano Barbacid got his Ph.D. in Madrid’s Universidad Complutense (1974) and trained as a postdoctoral fellow at the US National Cancer Institute (1974-78). In 1978, he started his own research group to study the molecular events responsible for the development of human tumours. His work led in 1982, to the isolation of the first human oncogene and the identification of the first mutation associated with the development of human cancer. These findings, also made independently by two other groups, have been seminal to establish the molecular bases of human cancer.In 1988, he joined Bristol Myers-Squibb where he became Vice President, Oncology Drug Discovery. In this position, he pioneered the development of what we know now as targeted therapies. In 1998, he returned to Madrid to create and direct the Spanish National Cancer Research Center (CNIO). In 2011, Barbacid stepped down as director to return to his early research interests and lead his research group 'Oncología Molecular' at CNIO.

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