Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)...Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

By screening 31 drugs with 110 targets, FNTA, HSPA5, NEU1, CCND1, CASP1, CASP3 were negatively correlated with ovarian cancer, and HMGCR, PLA2G4A, ITGAL, PTGS1, FNTB were positively correlated with ovarian cancer. Statins (HMGCR blockers), lonafarnib (farnesyltransferase inhibitors), the anti-inflammatory drug aspirin, and the anti-malarial drug adiponectin all have potential therapeutic roles in ovarian cancer treatment.

P2, N=5, Active, not recruiting, National Cancer Institute (NCI) | N=49 --> 5 | Trial completion date: Sep 2027 --> Apr 2025 | Trial primary completion date: Sep 2027 --> Mar 2024

This study constructed a mRNAsi and HAGs-related prognostic model, which has implications for potential immunotherapy and drug treatment of LIHC.

P2, N=9, Terminated, Spanish Lung Cancer Group | Active, not recruiting --> Terminated; The recruitment was closed prematurely to due to slow recruitment.

This review sheds light on the prevalence of H-Ras mutations, their association with clinical characteristics, and their potential implications for OSCC prognosis. It also enhances our comprehension of the molecular mechanisms that underlie OSCC and paves the way for further research into targeted treatments based on H-Ras alterations.

Notably, the low-risk group exhibited higher sensitivity to epothilone.B, metformin, and tipifarnib compared to the high-risk group. The nomogram incorporating these factors demonstrated improved performance in predicting gastric cancer prognosis. Our study established risk features derived from GARGs that hold potential clinical utility in prognostic assessment and immune therapy response evaluation of gastric cancer patients.

Accordingly, we have tested FTIs (tipifarnib and lonafarnib) in G12C mutant human cancer cell lines in vitro and in vivo. At last, we have also tested FTIs on G12V mutant human cancer cells and again we have detected antitumoral effects. We suggest that FTIs may have clinical relevance outside the HRAS mutant cancers.

Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.

Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven HNSCC.

Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations.

P2, N=49, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

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

The prognostic indicators reported here could be considered as a resource for identifying tumorigenesis and chemoresistance to farnesyltransferase inhibitor. They could help identify important research directions for the development of new prognostic and therapeutic techniques for AML.

Using an impressive array of in vitro and in vivo preclinical HNSCC models, Smith and colleagues demonstrated the efficacy of alpelisib and tipifarnib combination therapy through sustained mTOR inhibition in PIK3CA/HRAS-dysregulated HNSCC, including preliminary evidence of robust antitumor activity in a patient enrolled in a precision medicine trial. This study in this issue of Cancer Research illustrates the value of preclinical avatars for informing biomarker-driven clinical trials to advance precision medicine in HNSCC and other cancers. See related article by Smith et al., p. 3252.

HCC patients with high risk were correlated with shorter survival time, immune evasion, tumor stem cell characteristics and high sensitivity to Tipifarnib and Camptothecin drugs. Hepatocellular carcinoma prognosis was predicted by an E2F target signature. This finding establishes the theoretical usefulness of the E2F target route in customized identification and treatment for future research.

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

The drug sensitivity analysis showed the high-expression subgroup may be more susceptible to Bexarotene, Doxorubicin, Gemcitabine and Tipifarnib. It may be related to the immunosuppressive microenvironment and could be an underlying HCC treatment strategy. However, the conclusions still require further validation studies.

Recently, several preclinical and clinical advancements have been made in the implementation of small-molecule inhibitors that block post-translational farnesylation of HRas, thereby abrogating its downstream oncogenic activity. In this review, we focus on the biology of wild-type and mutant HRas signaling in HNSCC, and rationale for use and outcomes of farnesyltransferase inhibitors in patients with HRAS-mutant tumors.

We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors. Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.

No abstract available

Many once-promising therapies such as tipifarnib, an inhibitor of Ras signaling, have failed clinically. Likewise, phase II clinical trials with erlotinib, which targets the epidermal growth factor (EFGR), and sorafenib, which targets the vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor (PDGF), and Raf, in combination with standard chemotherapy, have also failed to produce a response in patients...We then describe how to perform genome-scale shRNA screens to identify and compare critical signaling pathways in mouse and human MPNST cells and identify druggable targets in these pathways. These methodologies provide an effective approach to identifying new therapeutic targets in a variety of human cancer types.

In drug sensitivity analysis, the high-risk subgroup had a considerably lower TIDE score, suggesting a preferable response to immunotherapy, and may be more sensitive to Tipifarnib, Imatinib, Doxorubicin, and Gemcitabine. The patients with the higher PANRG-score may carry a dismal survival and relatively low immune infiltration, but a potential better immunotherapy response. Therefore, future HCC therapy perspectives should emphasize the setting of PANoptosis to achieve a personalized, practicable and effective therapeutic regimen.

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

The discovery of the entry inhibitor bulevirtide has represented a breakthrough in HDV treatment, by demonstrating high rates of viral suppression in phase II and III trials, results which have been confirmed in real-world settings and in patients with compensated advanced liver disease. In the meantime, other compounds (i.e. lonafarnib, new anti-hepatitis B virus drugs) are under development to provide alternative or combined strategies for HDV cure. The first international Delta Cure meeting was organised in Milan in October 2022 with the aim of sharing and disseminating the latest data; this review summarises key takeaway messages from state-of-the-art lectures and research data on HDV.

Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high-fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

This makes the management of HDV a challenge for physicians. In this review, we look at the background, diagnosis and treatment of HDV, informed by our hospital data, to set out the optimal management of HDV; we also explore novel treatment options for this disease.

Tipifarnib is the first targeted therapy for this rare HNSCC subset. Ongoing combination studies are targeting adaptive resistance pathways (PI3K/mTOR/Akt) to further improve outcomes.

In the N-nitroso-N-methylurea-induced ER positive rat breast model (50%HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, epidermal growth factor receptor inhibitors, and retinoid X receptor agonists are profoundly effective in prevention and interception of tumors with wild type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS.

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.

Tipifarnib is the first in the class of farnesyl transferase inhibitors to show efficacy in HRAS -mutated RM HNSCC. The understanding of mechanisms of resistance will pave the way for the design of second-generation farnesyl transferases inhibitors.

We report 48% of NEN with a putative actionable MA of which 35% received molecularly matched treatment, with a clinical benefit in 67% of the cases.

Tipifarnib treatment also reduced AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.

No abstract available

P2, N=9, Active, not recruiting, Spanish Lung Cancer Group | Trial completion date: Oct 2023 --> Jul 2023 | Trial primary completion date: Jan 2023 --> Oct 2022

P1, N=0, Withdrawn, Kura Oncology, Inc. | N=50 --> 0 | Recruiting --> Withdrawn