- Theme 1: Determining the impact of germline genetics on cancer susceptibility, progression, treatment choices, and response.
- Theme 2: Exploiting somatic tumor genomic events for precision medicine drug development and targeted therapy.
- Theme 3: Developing new biological insights and combinatorial therapies through systems views of cancer.
Theme 1: Determining the impact of germline genetics on cancer susceptibility, progression, treatment choices, and response.
Margaret Wrensch, PhD; Paige Bracci, PhD, MPH, MS; Joe Wiemels, PhD ; and John Wiencke, PhD, and Kyle Walsh, PhD (former CG Program member) have continued to make central discoveries that are helping to decipher the genetic basis of adult gliomas . Most recently, they have led large-scale projects that identified genetic variants that define several brain tumor subtypes with differing survival profiles. They further showed that variants in TERC and TERT help drive telomere length. This important work demonstrated that germline SNPs in genes that affect the length of telomeres are important susceptibility factors for glioma. Their data motivate future work on the potential biological and translational mechanisms underlying development of cancer due to genetic instability arising from disruption of telomere length, and form a natural bridge to the work by the group of Boris Bastian, MD, PhD described below. Bastian, Executive Director of the new UCSF Clinical Cancer Genomics Laboratory (CCGL), has continued to make groundbreaking discoveries that illuminate the genetic changes in different subtypes of melanoma. In the first study of its kind, he carried out a dissection of the progressive events in melanomas from the earliest lesions through to metastasis, identifying TERT promoter mutations at a surprisingly early stage in neoplastic progression. TERT promoter mutations are also highly prevalent in gliomas, as shown by NE Program member Joseph Costello, PhD, and have led to development of a start-up company (Telo Therapeutics) with the goal of developing novel drugs that target the effects of these mutations. These studies have redefined the genetics of melanoma development and progression, identifying recurrent mutations or novel gene fusions in several targets (GNAQ, GNA11, c-KIT, BRAF, NTRK3) that provide new opportunities for translational applications in prevention and treatment.
Theme 2: Exploiting somatic tumor genomic events for precision medicine drug development and targeted therapy.
Allan Balmain, PhD, FRS, David Quigley, PhD, and international collaborators compared the genetic architecture of mouse tumors induced by exogenous mutagens, and those arising in genetically engineered cancer models. They demonstrated that chemically induced tumors mimic much more closely the patterns of changes found in equivalent human cancers. The data have revived interest in environmentally induced tumors as models for cancer therapy, in particular for immunotherapy, which is dependent largely on a high mutation burden. They further demonstrated that tumors induced by chemical mutagens carry the genome-wide mutation signatures of exposure. These results led to the award of a major $30M grant from Cancer Research UK to a consortium of several institutions, including UCSF, in which Balmain is playing a key leadership role to carry out a sequencing initiative to identify mutation signatures in mouse and human cancers.
Theme 3: Developing new biological insights and combinatorial therapies through systems views of cancer.
Trever Bivona, MD, PhD is analyzing the genetics and responses of human cancers to targeted therapies. Bivona collaborated extensively with Eric Collisson, MD and Martin McMahon, PhD (former ET Program member) to show that the Hippo effector YAP, Anaplastic Lymphoma Kinase (ALK), or AXL kinase promote resistance to EGFR/Ras/Raf-targeted cancer therapies. These data offer new possibilities to prevent or reverse drug resistance using combined or sequential treatment with clinically approved inhibitors of EGFR/Ras signaling and novel agents targeting the Hippo/YAP pathway.