Exploiting genomic vulnerabilities in leiomyosarcoma
Cell Biology
Final Report Abstract
Leiomyosarcoma (LMS) is a rare but aggressive cancer that originates from smooth muscle cells, commonly affecting areas like the abdomen, blood vessels, and the uterus. Treatment usually involves surgical removal of the tumor and may include radiation therapy. However, when the disease spreads, treatment options become more complex and often less effective. This project focused on understanding and improving treatments for LMS, particularly when it has spread beyond the initial site. LMS cells demonstrate high level of genomic complexity, which means these cells often have abnormal numbers and structures of chromosomes. This instability can make the cancer more aggressive and harder to treat but also offers a potential vulnerability we can target with specific therapies. This project contributed to the field with two key observations: Firstly, we found that a factor needed for DNA repair, DNA-PK, is essential for LMS cell survival, but not as important in other cancers. This highlights it as specific vulnerability in LMS for which an inhibitor drug exists. Secondly, we found out that DNA-PK inhibition mitigates tumor growth and that it can be safely combined with low-dose Doxorubicin, a chemotherapy drug commonly used to treat sarcomas. This combination potentiated the effects of DNA-PK inhibition in cell cultures and animal models. Whether defects in other DNA-damage repair pathways (such as homologous recombination repair) contribute to DNA-PK dependency is currently unknown and being addressed in followup studies. Our findings led to a clinical phase I trial, which is testing the combination of a DNA-PK inhibitor in combination with low-dose pegylated Doxorubicin in patients with LMS and biologically similar sarcomas. The correlative science in this trial will help to further characterize DNA damage response in sarcoma and identify potential resistance mechanisms.
Publications
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Leiomyosarcoma: Does Location of Primary Help to Determine the Best Systemic Therapy Options?. Current Treatment Options in Oncology, 22(11).
Novotny, Jan Philipp & George, Suzanne
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Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma. Clinical Cancer Research, 29(24), 5128-5139.
Marino-Enriquez, Adrian; Novotny, Jan Philipp; Gulhan, Doga C.; Klooster, Isabella; Tran, Antuan V.; Kasbo, Macy; Lundberg, Meijun Z.; Ou, Wen-Bin; Tao, Derrick L.; Pilco-Janeta, Daniel F.; Mao, Victor Y.; Zenke, Frank T.; Leeper, Brittaney A.; Gokhale, Prafulla C.; Cowley, Glenn S.; Baker, Laurence H.; Ballman, Karla V.; Root, David E.; Albers, Joachim ... & Fletcher, Jonathan A.
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Targeting DNA-PK. Cancer Treatment and Research, 299-312. Springer International Publishing.
Novotny, Jan Philipp; Mariño-Enríquez, Adrian & Fletcher, Jonathan A.
