Dual targeting of CDK4/6 and PI3K/mTOR in high-risk osteosarcoma

In children, adolescents, and young adults (AYA), osteosarcoma (OS) is the most common type of bone cancer. Approximately 25-50% of OS patients have metastatic lesions at the time of diagnosis and no standard second-line therapies currently exist. In patients that survive cancer in their younger years, up to 95% can develop chronic health problems due to the chemotherapy. Thus, there is a critical need to identify therapies that do not use chemotherapy but rather inhibit specific molecular signatures in OS. Hyperactivation of cyclin-dependent kinases 4 and 6 (CDK4/6) which promotes cell growth has been identified by our team and others as a therapeutic target in OS. While CDK4/6 inhibitors show promise in clinical trials for cancer, resistance to CDK4/6 inhibition can emerge by activation of additional growth promoting pathways such as PI3K/mTOR. However, no studies have evaluated how to best use CDK4/6 and PI3K/mTOR inhibitors in combination to treat OS. Our data indicate that in a human tumor model of relapsed OS, a combination therapy inhibiting CDK4/6 and PI3K/mTOR was well-tolerated and significantly blocked tumor growth. We now propose to evaluate this therapy in a panel of high-risk OS pediatric and AYA models. We hypothesize that dual inhibition of CDK4/6 and PI3K/AKT/mTOR pathway will be efficacious and well-tolerated in models of pediatric and AYA OS. This hypothesis will be tested in the following specific aims (SA): SA1: Evaluate efficacy, safety, and underlying adaptive responses of single or dual inhibition of CDK4/6 and PI3K/mTOR in OS tumor models with hyperactivation of CDK4/6. SA2: Assess influence of the tumor microenvironment on OS tumor response following single or dual inhibition of CDK4/6 and PI3K/mTOR. Retinoblastoma-1 proficient (RB+) pediatric and AYA OS patient tumor models with high-risk molecular signatures indicating hyperactivation of CDK4/6 and PI3K/mTOR were developed from consented patients seen at our institution (HT96 and TT2). RB+ is required for cell growth via CDK4/6 and serves as a biomarker of response to CDK4/CDK6 inhibitors. Tumor microenvironment can influence OS growth and response to therapy. OS tumors typically grow inside and outside the bone and routinely metastasize to the lung. Therefore, tumor response in bone/intratibial OS and metastatic OS-lung models will also be determined. We will compare efficacy and safety of frontline therapy to single inhibitor and dual inhibitor therapy. Tumor samples will be analyzed at the gene and protein levels to gain an understanding of the underlying tumor response to therapy. Significance. The long-term goal of our research is to obtain strong rationale for earlier intervention using targeted agents in OS patients with high-risk molecular signatures. Information on tumor responses may lead to innovative therapeutic approaches and inform a future clinical trial targeting CDK4/6 and PI3K/mTOR pathways in pediatric and AYA OS patients.