AACR-Novocure Grantees’ Collaboration Plants the Seeds for Future Therapeutics
In 2019, Michael D. Story, PhD, vice chair of the Department of Radiation Oncology and chief of the Division of Molecular Radiation Biology at UT Southwestern Medical Center, was one of the inaugural recipients of the AACR-Novocure Tumor Treating Fields (TTFields) Research Grants Program. Now in 2020, he has the pleasure of seeing his mentee, Narasimha Kumar Karanam, PhD, receive an AACR-Novocure Career Development Award for Tumor Treating Fields Research.
The two researchers have been working together since 2012, when Karanam joined Story’s laboratory as a postdoctoral fellow to study the role of microRNAs (miRNAs) in advanced head and neck cancer. “The TTFields project was already ongoing,” recalls Karanam, “and I was really fascinated by its innovative and translational potential.” After he finished the miRNA project, he switched his focus to TTFields.
The collaboration between Story and Karanam on TTFields research has been fruitful. They have already published some of their work in Cell Death & Disease and Translational Research. “We have shown for the first time mechanistically that TTFields treatment indeed affects DNA damage and replication stress pathways,” explains Karanam, “and that these defects in DNA damage and replication stress pathways occur simultaneously to mitotic aberrations.” These findings represent a significant development in the understanding of TTFields’ mechanisms of action beyond the disruption of mitosis (previously discussed in this blog post).
Their findings also have important implications for clinical strategies related to the application of TTFields in combination with other cancer treatment modalities. In vitro studies conducted by Story and Karanam suggest that using TTFields before radiation is more effective than applying TTFields after radiation. “We believe that TTFields treatment induces conditional vulnerabilities in cancer cells,” Karanam says, “so they become more sensitive to additional radiotherapy or chemotherapy.” This idea has already been translated into clinical trials: PriCoTTF is presently testing the efficacy of TTFields treatment prior and concomitant to radiation therapy, while TRIDENT will assess TTFields treatment concurrently with radiation and chemotherapy.
Story and Karanam continue to collaborate while working on their individual but complementary AACR-Novocure funded grant projects. Story is exploring the therapeutic potential of combining TTFields with chemotherapeutic agents that increase replication stress in both in vitro and ex vivo models of lung and pancreatic cancers. Karanam’s project is also therapeutically oriented, but with a focus on identifying upstream factors that increase replication stress and damage DNA under TTFields exposure. In addition, he is looking at the proteomic and metabolomic changes that occur after TTFields treatment, a new and exciting direction for TTFields research.
Both Story and Karanam hope that their work will lead to future clinical trials for novel combinatorial therapeutics involving TTFields. “It is especially gratifying to see your findings begin to be translated to clinical applications,” says Story. “Even if it is not a one-to-one transfer, you can see the seed planted by your work.” Story and Karanam’s work truly embodies the aims of the AACR-Novocure grants partnership: to provide a deeper understanding of the mechanisms of action of TTFields and to accelerate the development of new treatment strategies for cancer.
For a third year, the AACR and Novocure, a global oncology company, are pleased to again offer funding opportunities for TTFields research. Applications are currently being accepted for the 2021 AACR-Novocure Career Development Awards for Tumor Treating Fields Research and the 2021 AACR-Novocure Tumor Treating Fields Research Grants. The deadline for submission is January 12, 2021. Please visit the AACR’s funding page for more information.
Editor’s note: Michael D. Story, PhD, and Narasimha Kumar Karanam, PhD, work on research sponsored by Novocure. Story has previously been compensated by Novocure for speaking and for organizing user meetings.