Pre-Clinical Development of Synergistic Drug Combinations Studies Targeting DNA Damage Response Inhibitors in Leiomyosarcoma
| Leiomyosarcoma (LMS) is a common type of adult sarcoma that arises from smooth muscle, which is only cured by surgery. Unfortunately, 50% of patients do not survive as they develop metastasis or spread of the cancer from the original site of LMS, as standard drug therapy is largely ineffective. Importantly, this disease arises in both the uterus and soft tissues including the abdomen and extremities. Historically, drug development has focused on one or the other patient groups (uterine vs. non-uterine) but we believe in understanding what common biology and hence drugs could work in both groups of patients. In this one-year grant application, we propose to continue our work on using a panel of well characterized LMS cell lines to prioritize new drug combinations that show promise. Specifically, we identified and plan on testing at least 2 new drug combinations – standard chemotherapy – doxorubicin with a more precise drug – known as a “targeted agent” for patients with LMS. Previous work in our Sarcoma Translational Research Laboratory has uncovered that certain types of selective drugs – those that target a specific type of DNA damage called Homologous Recombination (HR) – are effective in the majority of our LMS patient derived cell lines. Thus, we seek in this study to better understand why most patients respond while others don’t and also to work on when the drugs stop working, which is called resistance. To address these important questions, we have two Aims: Aim 1: To evaluate why some LMS cell lines respond, and others don’t to standard chemotherapy plus these emerging selective drugs that target parts of HR. To address this, we will perform standards tests in the lab to understand why the drugs work and why they don’t. Also, we have developed cell lines that are resistant to doxorubicin, the current standard drug in LMS. We will evaluate if the new drugs can overcome this blockade and if they do, how this works. Aim 2: We will work on understanding why a new promising drug combination doxorubicin and a newer drug trabectedin works in some LMS patients, which was recently published in a landmark clinical trial. Again, it is really critical before patients go into clinical trials, if we can predict that they may or may not respond, as we hope to provide more tailored therapy that would work for patients as they get care. Importantly in these drug studies we will also test how they work in animal models so we can better determine response vs. not. Collectively, the information generated from this 1-year grant application will allow our team to work on the promise of new drug combinations for LMS patients. Also, we will evaluate across all sites of disease and finally we hope to be able to better predict which patients will respond vs not. Data from this work will allow our team to better design clinical trials, secure new larger team grants and establish partnerships with pharma. |