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8 results on '"Patel, Hetika"'

1. Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity

Author

Smith, Alison E, Chan, Stacia, Wang, Zhiyong, McCloskey, Asako, Reilly, Quinn, Wang, Jayden Z, Patel, Hetika Vora, Koshizuka, Keiichi, Soifer, Harris S, Kessler, Linda, Dayoub, Ashley, Villaflor, Victoria, Adkins, Douglas R, Bruce, Justine Y, Ho, Alan L, Perez, Cesar A, Hanna, Glenn J, Hernandez, Amaya Gasco, Saunders, Andrew, Dale, Stephen, Gutkind, J Silvio, Burrows, Francis, and Malik, Shivani

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Dental/Oral and Craniofacial Disease, Cancer, Orphan Drug, Rare Diseases, Humans, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell, Neoplasm Recurrence, Local, TOR Serine-Threonine Kinases, Head and Neck Neoplasms, Class I Phosphatidylinositol 3-Kinases, Biomarkers, Proto-Oncogene Proteins p21(ras), Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.SignificanceThe mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.

Published
2023

2. Supplementary figures S1-S5 from Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity

Author

Smith, Alison E., primary, Chan, Stacia, primary, Wang, Zhiyong, primary, McCloskey, Asako, primary, Reilly, Quinn, primary, Wang, Jayden Z., primary, Patel, Hetika Vora, primary, Koshizuka, Keiichi, primary, Soifer, Harris S., primary, Kessler, Linda, primary, Dayoub, Ashley, primary, Villaflor, Victoria, primary, Adkins, Douglas R., primary, Bruce, Justine Y., primary, Ho, Alan L., primary, Perez, Cesar A., primary, Hanna, Glenn J., primary, Gascó Hernández, Amaya, primary, Saunders, Andrew, primary, Dale, Stephen, primary, Gutkind, J. Silvio, primary, Burrows, Francis, primary, and Malik, Shivani, primary

Published
2023
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3. Data from Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity

Author

Smith, Alison E., primary, Chan, Stacia, primary, Wang, Zhiyong, primary, McCloskey, Asako, primary, Reilly, Quinn, primary, Wang, Jayden Z., primary, Patel, Hetika Vora, primary, Koshizuka, Keiichi, primary, Soifer, Harris S., primary, Kessler, Linda, primary, Dayoub, Ashley, primary, Villaflor, Victoria, primary, Adkins, Douglas R., primary, Bruce, Justine Y., primary, Ho, Alan L., primary, Perez, Cesar A., primary, Hanna, Glenn J., primary, Gascó Hernández, Amaya, primary, Saunders, Andrew, primary, Dale, Stephen, primary, Gutkind, J. Silvio, primary, Burrows, Francis, primary, and Malik, Shivani, primary

Published
2023
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6. Tipifarnib potentiates the antitumor effects of PI3Kα inhibition inPIK3CA- andHRAS-dysregulated HNSCC via convergent inhibition of mTOR activity

Author

Smith, Alison E., primary, Chan, Stacia, additional, Wang, Zhiyong, additional, McCloskey, Asako, additional, Reilly, Quinn, additional, Wang, Jayden Z., additional, Patel, Hetika Vora, additional, Koshizuka, Keiichi, additional, Soifer, Harris S., additional, Kessler, Linda, additional, Dayoub, Ashley, additional, Villaflor, Victoria, additional, Adkins, Douglas, additional, Bruce, Justine, additional, Ho, Alan, additional, Batista, Cesar Perez, additional, Hanna, Glenn, additional, Gascó Hernández, Amaya, additional, Saunders, Andrew, additional, Dale, Stephen, additional, Gutkind, J. Silvio, additional, Burrows, Francis, additional, and Malik, Shivani, additional

Published
2023
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