Preliminary results from a phase II trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutations

Ho, Alan L.; Chau, Nicole G.; Bauman, Jessica R.; Bible, Keith C.; Chintakuntlawar, Ashish V.; Cabanillas, Maria E.; Wong, Deborah J.; Garcia, I. Braña; Brose, Marcia S.; Boni, Valentina; Even, Caroline; Razaq, Mohammad; Mishra, Vasudha; Bracken, Karen; Wages, David; Scholz, Claus Jürgen; Gualberto, Antonio

doi:10.1093/annonc/mdy287.002

Cited by 22 publications

(19 citation statements)

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“…Because its reintroduction into the clinic in 2015, several cohorts of HRAS-mutant patients have been treated in a single-arm phase II trial (NCT02383927), with encouraging preliminary findings. As reported in 2018 (45,50), among 7 evaluable patients with HNSCC, 5 (71%) achieved a confirmed partial response with a median duration of response of 14.1 months. Importantly, no HRAS-mutant HNSCC patient experienced an objective response on his last therapy prior to receiving tipifarnib (including platinum, immunotherapy and cetuximab AE chemotherapy regimens).…”

Section: Discussionsupporting

confidence: 57%

Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas

Gilardi

Wang

Proietto

et al. 2020

Molecular Cancer Therapeutics

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Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRASmutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Here, we report the characterization of tipifarnib activity in a wide panel of HRAS-mutant and wild-type head and neck squamous cell carcinoma (HNSCC) xenograft models. Tipifarnib treatment displaced both mutant and wild-type HRAS from membranes but only inhibited proliferation, survival, and spheroid formation of HRAS-mutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRASmutant xenografts tested but displayed no activity in six HRAS wild-type patient-derived xenograft (PDX) models. Mechanistically, drug treatment resulted in the reduction of MAPK pathway signaling, inhibition of proliferation, induction of apoptosis, and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FTase inhibition induces progressive squamous cell differentiation in tipifarnibtreated HNSCC PDXs. These preclinical findings support that HRAS represents a druggable oncogene in HNSCC through FTase inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.

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Section: Discussionsupporting

confidence: 57%

Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas

Gilardi

Wang

Proietto

et al. 2020

Molecular Cancer Therapeutics

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“…This observation might be important for the design of targeted therapy trials in the perioperative setting of UTUC or in the selection of the tumor types to include in umbrella and basket studies. As an example, tipifarnib was effective in treating HRAS-mutant head and neck squamous-cell carcinoma in a phase 2 trial [24].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma

Necchi

Madison²,

Pal

et al. 2021

European Urology Focus

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“…Inhibition of farnesyl transferase activity produced antitumor activity in preclinical models of SCC of the skin with HRAS mutations, an antitumor effect that was not observed in models with NRAS or KRAS mutations (57). Tipifarnib, a farnesyl transferase inhibitor is currently tested in a phase 2 study in advanced tumors with activating mutations of HRAS (58). Preliminary reports of 7 evaluable SCCHN showed 5 patients (71%) achieving a partial response with a median duration of response of 14.1 months.…”

Section: Other Molecular Targetsmentioning

confidence: 99%

Beyond EGFR Targeting in SCCHN: Angiogenesis, PI3K, and Other Molecular Targets

Sâada-Bouzid

Tourneau

2019

Front. Oncol.

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Although the molecular landscape of squamous cell carcinoma of the head and neck (SCCHN) has been largely deciphered, only one targeted therapy has been approved to date without any molecular selection, namely cetuximab. Cetuximab is a monoclonal antibody targeting EGFR. It has been shown to improve overall survival in the locally advanced setting in combination with radiotherapy and the recurrent and/or metastatic setting in combination with a platinum compound and 5FU. Beside EGFR targeting agents, antiangiogenic agents have been shown to produce antitumor activity but were associated with substantial toxicity. Buparlisib that targets PI3K was also shown to improve survival in combination with paclitaxel in an unselected patient population. Several other targeted therapies have been developed in SCCHN, most of time in all comers, potentially explaining the limited efficacy reported with them. The recent emergence of clinical trials of targeted therapies in enriched patient populations and precision medicine trials such as umbrella trials might boost the clinical development of targeted therapy in SCCHN.

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Preliminary results from a phase II trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutations

Cited by 22 publications

References 0 publications

Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas

Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas

Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma

Beyond EGFR Targeting in SCCHN: Angiogenesis, PI3K, and Other Molecular Targets

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