Valsamo Anagnostou: Here’s the latest from the Johns Hopkins Kimmel Cancer Center Molecular Tumor Board

Valsamo Anagnostou, Associate Professor of Oncology at The Johns Hopkins University School of Medicine, made the following post on LinkedIn:

“Here’s the latest from the Johns Hopkins Kimmel Cancer Center Molecular Tumor Board, hot off the press in Frontiers in Medicine and arising from questions and discussions during our weekly molecular tumor board meetings: Why is there a disconnect between the presence of targetable mutations and therapeutic efficacy of genotype-matched targeted therapies for patients with high-grade gliomas?

Our star Molecular Tumor Board fellows Paola Ghanem and Maria Fatteh took a deep dive into the genomic landscape of glioblastomas to understand the clonal heterogeneity of these tumors and found the highest density of subclonal mutations affecting hotspots in glioblastomas compared to other tumors.

Guided by the unique insights of Skip Grossman, Karisa Schreck, and David Olayinka Kamson, they then looked into a large array of biochemical features of targeted therapies paired with frequently occurring mutations in glioblastoma and found that – somewhat contrary to our current thinking – the drugs’ half-life, molecular weight, surface area, and binding to efflux transporters were not associated with clinical efficacy. A trend towards higher lipid solubility and lower IC50 in glioblastoma cell lines was associated with clinical efficacy of glioblastoma mutation-targeted therapies, as assessed in clinical trials.

These findings were instrumental in interpreting clinical outcomes of our real-world data Molecular Tumor Board cohort of patients with high-grade gliomas, leveraging the expertise of master clinicians Jenna Canzoniero and Jessica Tao and our neuro-oncology group. These analyses showed that patients matched to genotype-tailored therapies had better clinical outcomes compared to the ones that harbored putatively actionable alterations that did not receive genotype-targeted therapies.

This work highlights the challenges and opportunities of genotype-targeted therapies for patients with brain tumors. In making therapeutic decisions, we have to take into account the host, tumor, and drug-related features that may limit the delivery and efficacy of targeted therapies.

We wanted to thank our patients, their families, and all the Hopkins Molecular Tumor Board investigators that have made this – and all our – research possible: Chris Gocke, Rena Xian, Ming-Tseh Lin, Christine Pratilas, Vered Stearns, Taxiarchis Botsis, Kory Kreimeyer, Katie Fiallos (Waldeck), Dana Petry, Kala Visvanathan, MD, MHS, Antonio C. Wolff, Cesar Santa-Maria, Christian Meyer, MD PhD, John Laterra, Deb Armstrong, Rachel Karchin, Katerina Karaindrou, Marta Majcherska-Agrawal, Faith Too, Monique Makell, Jennifer Lehman, Timsy Wanchoo, Jaime Wehr, Michael Conroy, Selina Shiqing Teh, Marina Baretti.”

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Source: Valsamo Anagnostou/LinkedIn