HRAS overexpression

Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

A CRISPR/Cas9-based method for inducing GIC is much more efficient than a KO mice-based method. This study provides a promising framework for easily creating glioblastoma model in mice.

P1, N=270, Recruiting, Kura Oncology, Inc.

P1, N=270, Recruiting, Kura Oncology, Inc. | Not yet recruiting --> Recruiting

P1, N=270, Not yet recruiting, Kura Oncology, Inc.

ΔNp63α/v-ras-driven carcinomas expressed higher levels of chemokines implicated in recruitment of MDSCs compared to v-ras-initiated tumors, providing a heretofore undescribed link between ΔNp63α/HRAS-driven carcinomas and the development of an immunosuppressive TME. These results support the utilization of a genetic carcinogenesis model harboring specific genomic drivers of malignancy to study mechanisms underlying the development of local immunosuppression.

One patient each was treated with immune checkpoint inhibition (Mixed Response) and combination therapies of tipifarnib and ADT (SD) and alpelisib and ADT (PR). Combination therapies, PI3K-inhibitors and immune therapy warrant further investigation, ideally in clinical trials. Future research should consider this rare subgroup of SDC.

Combined alpelisib and tipifarnib has potential to benefit >45% of R/M HNSCC patients. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.

Lenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome.

All observed/available data among each cohort will be evaluated before choosing the combination dose for a subsequent cohort. Enrollment into the PIK3CA cohort began in October 2021.