This application addresses the following Lung Cancer Research Program areas of emphasis: (1) Identifying innovative strategies for treatment of early and/or localized lung cancer and (2) understanding susceptibility or resistance to treatment.
Detailed epidemiological studies that examined the death rate of Veterans due to lung cancer have shown that the mortality rate for lung cancer among Veterans was double that of civilians. This abnormally high rate of lung cancer deaths was predominantly attributed to tobacco smoking. Since many of the Veterans who currently smoke, as well as those who have given up smoking but smoked in the past, are still at risk of developing lung cancer, it is important that we find targeted therapies for lung cancer that arises from smoking. The last decade has witnessed a major paradigm shift in the treatment of lung cancer because of the identification of several genetic mutations in oncogenes that have been found to be associated with this form of cancer. Some of the genes mutated in lung cancer include KRAS, PI3KCA, CTNNB1, ROS, RAF, RET, HER2, FGFR1, MET and PDGFRA. Of these, KRAS is the most frequently mutated oncogene (occurring in approximately 25% of adenocarcinomas) and is most often associated with patients with a smoking history. While therapies targeted against EGFR and ALK have already been approved by the Food and Drug Administration (FDA), targeted therapies against RAS do not exist.
Unfortunately, the development of RAS inhibitors has been challenging due to the lack of well-defined cavities on the RAS surface that would allow a drug to bind. It is well established that RAS transmits its signals by binding to a large number of cellular proteins that contain a protein domain called the RAS-binding domain (RBD). The interaction of RAS with RBDs is essential for its function. Since all RAS-interacting proteins (called RAS-effector proteins) share this RAS-binding motif, we undertook a novel strategy of developing compounds that target the RBDs of RAS-binding proteins (on which more suitable binding pockets appear to be present) with the hope that we could identify a molecule that could prevent the binding of RAS to its effectors. Towards this goal, we synthesized a compound library of approximately 4,000 molecules and screened this library for compounds that bind to the RBD domain of RAS effector proteins. After lead optimization, we carried out extensive characterization of two of the compounds, rigosertib and 015040, and discovered that these compounds bind to RBDs of multiple RAS effectors with high affinity and block their interaction with RAS, thereby shutting down RAS function in tumor cells. Rigosertib is orally bio-available with an excellent safety profile and is currently in Phase III clinical trials for the treatment of myelodysplastic syndrome (MDS). We expect 015040 to reach clinical trials in 1-2 years’ time.
Based on our preliminary studies, we propose that rigosertib and 015040 bind to the RBDs of multiple RAS effectors and disrupt mutant RAS-mediated signaling. It is our hypothesis that rigosertib and 015040 will effectively overcome the deleterious effects of tumorigenic KRAS mutations in lung cancer.
To prove this hypothesis, we propose to examine the effects of these two compounds on the growth of lung tumors using two different mouse models. In the first model, we will examine the effects of rigosertib and 015040 on the growth of lung tumors using Patient-Derived Xenograft (PDX) models. The Jackson Laboratory has an extensive collection of early passage lung tumors, which harbor various mutations including KRAS. We will also examine the effects of rigosertib and 015040 on the growth of lung tumors using Genetically Engineered Mouse (GEM) models that harbor KRAS mutation and develop adenocarcinomas of the lung. Recent studies with different lung cancers have shown that these tumors often evade the immunological response of the patient by expressing a protein called PD-L1 on their membrane. Antibodies against this protein and its receptor PD-1 have shown clinical efficacy in lung cancers and have been approved by the FDA for the treatment of lung cancers. In this application, we propose to test the combination of PD-L1 antibodies with our two RAS-inhibitors on lung cancer growth using our mouse models.
Impact: Currently, rigosertib is the only compound in clinical trials that has shown a capability to inhibit RAS oncogene-mediated growth signals by blocking its ability to interact with its partner proteins that transmit these tumorigenic signals. Importantly, this compound was found to inhibit mutated RAS gene functions and, hence, is an ideal drug for the treatment of KRAS-mutant lung cancers. In clinical trials, rigosertib has exhibited a very high degree of safety with minimal side effects, and if our proposed studies show efficacy in lung cancers, we can immediately start clinical trials to determine its efficacy in lung cancer patients that harbor KRAS mutations.