Precision Medicine and K-RAS mutant tumors: Deconstructing K-Ras signalling in lung and pancreatic cancer
Speaker: Mariano Barbacid, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
Time and location: May 6th at 13.30 MV Lecture Hall (Hörsalen), coffee and cake at 14.30.
Mariano Barbacid was awarded his Ph.D. from the Universidad Complutense, Madrid, in 1974. From 1974 to 1978 he trained as a postdoctoral fellow at the National Cancer Institute (NCI), Bethesda, Maryland, USA. In 1978 he started his own group to work on the molecular biology of human tumors. His work led to the isolation of the first human cancer gene, H-RAS, in the spring of 1982 and to the identification of the first mutation associated with the development of human cancer. In 1984, he moved to the NCI-Frederick, Maryland as Head of the Developmental Oncology Section and in 1988, he joined the Bristol Myers-Squibb Pharmaceutical Research Institute in Princeton, New Jersey where he became Vice President, Oncology Drug Discovery. In 1998, he returned to his native Madrid to create and direct the Spanish National Cancer Research Center (CNIO). He stepped down as Director in June 2011 to concentrate on his own research that currently focuses on the design of new animal models of cancer and on the identification and validation of molecular targets with potential therapeutic value. The relevance of his work has been recognized by many domestic and international awards and to date, Dr. Barbacid has authored 267 publications and has Hirsch "h" factor of 96.
KRAS oncogenes are responsible for the development of at least one fourth of all human tumors including lung and pancreatic adenocarcinomas, two tumors types with some of the worse prognosis. Unfortunately, development of suitable therapies to treat these tumors has remained elusive for the last thirty years and patients are still treated with old chemotherapy drugs. To address this important health issue, we decided to use genetically engineered mouse tumor models that closely recapitulate the natural history of these tumor types in order to deconstruct, by genetic means, oncogenic K-Ras signaling with the ultimate goal to identify molecular targets whose inhibition will result in therapeutic activity against advanced lung and pancreatic tumors. First, we have designed a new generation of mouse tumor models in which we can separate, both temporally and spatially, tumor induction from target inhibition. These new mouse tumor models make use of the yeast frt-FLp(o) recombinase system to induce cancer-driving mutations by inducing genomic recombination within their endogenous KRas and Trp53 cancer genes in either lung neumocytes or in their pancreatic acinar cells. In addition, these mice carry a transgene that encodes the bacterial CreERT2 inducible recombinase driven by the human Ubiquitin promoter which allows its expression in most, if not all, adult cells and tissues. Finally, these strains are used to introduce conditional knock-out or knock-in alleles of those molecular targets whose therapeutic potential we want to validate. Exposure of mice already bearing advanced tumors (as determined by imaging techniques) to a tamoxifen-containing diet results in the activation of inducible CreERT2 recombinase which
allows us to systemically ablate expression of the target or express inactive isoforms. This strategy makes it possible not only to evaluate the therapeutic consequences of ablating/inactivating selected targets, but to determine the potentially toxic effects derived from its systemic elimination or inactivation.
We have used this sophisticated experimental strategy to interrogate the therapeutic as well as potentially toxic consequences of ablating or inactivating each of the members of the MAPKinase cascade, including the Raf, Mek and Erk kinases, as well as key effectors of the PI3Kca. pathway including the PI3K p110alpha and mTOR. We have also evaluated additional upstream and downstream signaling elements, such as the EGF Receptor and the Cyclin-dependent kinases (Cdks) responsible for driving the cell cycle. This systematic approach has revealed that most of the K-Ras signaling effectors are not suitable therapeutic targets due to either lack of therapeutic activity, such as Cdk2, Cdk6 A-Raf or B-Raf, or to the induction of unacceptable toxicities such as the Mek1/2 and Erk1/2 kinases, PI3k p110alpha and Cdk1. Therefore, only c-Raf, EGFR and Cdk4 turned to be suitable therapeutic targets, based not only on their anti-tumor properties, but also on the well tolerated toxicities observed upon their systemic ablation/inactivation. In fact, ablation of c-Raf expression in advanced tumors driven by K-Ras/Trp53 mutations led to significant tumor regressions. Importantly, systemic abrogation of c-Raf expression did not inhibit canonical MAPK signaling, hence, resulting in limited toxicities (Sanclemente et al. Cancer Cell, 33: 217-228, 2018). We are now combining these targets to define more efficacious therapeutic strategies that could be eventually translated to the clinic. As a result of these studies, we have observed that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by KRas/Trp53 mutations in genetically engineered mice. Again, systemic elimination of these targets
induces toxicities that are well-tolerated. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts (PDX) carrying KRAS and TP53 mutations (Blasco et al. Cancer Cell, 35:573-587, 2019). These results should the door to the development of targeted therapies for patients carrying KRAS mutant lung and pancreatic tumors.
Carlos Rovira email@example.com