Treatment Options for Metastatic Osteosarcoma
Abstract
Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Pediatric, Adolescent, and Young Adult Cancers, Sarcoma, Metastatic Cancers. FY21 PRCRP Military Health Focus Area: Gaps in cancer treatment that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public. Scientific Objective and Rationale: The overall goal of our research is to validate a novel therapeutic strategy, CDK12 inhibition, for patients with metastatic osteosarcoma. Osteosarcoma is the most common bone tumor of adolescence and young adulthood. When the tumor is confined to the primary site (localized), for example, the long bones of the arm or leg, the 5-year survival rates are at a modest 70%. However, when the tumor cells have spread to the lung (metastasis), the survival rate falls to a dismal 30%, which has not changed appreciably over the last four decades despite coordinated, multi-national efforts to improve outcomes. Seven of every ten children who develop metastasis will succumb within 5 years. In fact, in 2021, patients with both localized and metastatic osteosarcoma are treated with the same chemotherapy regimen, based on large international group trials that showed no improvement in survival with increasing chemotherapy in the latter group. Thus, the resistance of lung metastasis lesions to current therapies and our inability to prevent metastases limit our capacity to save more of the lives affected by osteosarcoma. Developing new treatment options for osteosarcoma is challenging, because of the consistent lack of individual gene mutations that could be targeted with small molecule inhibitors. In addition, the chromosomes in osteosarcoma cells are scrambled with multiple breakages, losses, and gains, which together can cause DNA damage and a heavy reliance on repair mechanisms for cell survival. Thus, the genetic chaos that enables osteosarcoma cells to multiply uncontrollably also creates a vulnerability that could be exploited. We recently identified a gene, CDK12, that drives the expression of several DNA repair pathway genes. Using inhibitors developed by medicinal chemist and co-investigator, Dr. Nathanael Gray, we showed that CDK12 could be a drug target whose inhibition selectively kills osteosarcoma cells in the lung. CDK12 inhibition thus does not target a single gene mutation, but disrupts an entire process, DNA repair, in osteosarcoma cells. The excessive dependence of osteosarcoma cells on this process, makes them particularly vulnerable to this form of inhibition compared to normal cells. CDK12 inhibitors have demonstrated anti-tumor activity in other tumor models and we plan to test these in models of metastatic osteosarcoma. The overall goal of our research is to establish a preclinical rationale for the clinical testing of CDK12 inhibitors in metastatic osteosarcoma patients. Clinical/Translational Impact: Our proposal will address the FY21 PRCRP Overarching Challenge to transform cancer treatment through the identification of novel biomarkers and new targets especially for metastatic disease. We predict that the successful completion of these studies will have a positive impact on the adolescent/young adult (12-21 years old) patient population that is primarily affected by osteosarcoma. We intend, at the end of 4 years, to be in a position to present a solid case for instituting a clinical trial to test CDK12 inhibitors in metastatic osteosarcoma patients. CDK12 inhibitors are being developed by several pharmaceutical companies for use in adult cancers and the age of the majority of osteosarcoma patients (12-21 years), means that they do not have to wait for the adult trials to be completed to be entered into a trial. Moreover, the Principal Investigator, Dr. Rani George is a practicing pediatric oncologist and will be able to liaise with pharma companies to institute a clinical trial. In the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210855
Entities
People
- Rani George
Organizations
- Dana–Farber Cancer Institute
- United States Army