- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Trial completion date, Trial primary completion date, Metastases: Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS (clinicaltrials.gov) - Mar 30, 2023
P2, N=9, Active, not recruiting,
Trial completion date: Oct 2023 --> Jul 2023 | Trial primary completion date: Jan 2023 --> Oct 2022
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Zokinvy (lonafarnib) / Eiger
Journal: Effect of Farnesyltransferase Inhibitors on SARS-CoV-2. (Pubmed Central) - Mar 21, 2023
The understanding of mechanisms of resistance will pave the way for the design of second-generation farnesyl transferases inhibitors. The FTI lonafarnib and tipifarnib might be effective drugs against different SARS-CoV-2 strains.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, napabucasin (BBI608) / Sumitomo Pharma
STAT3 activation promotes invasiveness and cancer stemness in lung cancer (Section 16; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_8387;
Overall, our preliminary data identified STAT3 as a potential therapeutic vulnerability in highly invasive cancer cells. Future work will be focused on identifying pathways responsible to sensitize highly invasive NSCLC cells toward STAT3 inhibition using multiomics approach.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance (Section 43; Poster Board #23) - Mar 14, 2023 - Abstract #AACR2023AACR_2317;
In another example, tipifarnib has been demonstrated by others to inhibit the ability of tumor cells to enter a drug-tolerant state induced by the EGFR inhibitor, osimertinib, in EGFR-mutant NSCLC models...We have conducted in vitro 2D and 3D viability and regrowth experiments using combinations of tipifarnib with KRAS G12C inhibitors and have observed synergistic, anti-proliferative effects in KRAS G12C NSCLC cell lines as well as enhanced activity of combination in a KRAS G12C NSCLC PDX model. We are currently expanding the scope of in vitro and in vivo combination studies to further evaluate the molecular mechanism(s) of resistance that tipifarnib targets when combined with KRAS G12C inhibitors.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models (Section 43; Poster Board #15) - Mar 14, 2023 - Abstract #AACR2023AACR_2309;
Because FTIs are pleiotropic drugs, there are likely additional cell intrinsic mechanisms that may influence synergy with TKIs. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of TKI-tipifarnib effects and strengthen the therapeutic rationale for combining TKIs with tipifarnib in the treatment of patients with ccRCC.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Enrollment change, Trial withdrawal: Tipifarnib and Osimertinib in EGFR-mutated Non-Small Cell Lung Cancer (clinicaltrials.gov) - Mar 6, 2023
P1, N=0, Withdrawn,
Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of TKI-tipifarnib effects and strengthen the therapeutic rationale for combining TKIs with tipifarnib in the treatment of patients with ccRCC. N=50 --> 0 | Recruiting --> Withdrawn
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: HRAS Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma. (Pubmed Central) - Jan 6, 2023
Without targeted therapy, patients with HRAS-mutant HNSCC had poor clinic outcomes; observable trend toward improvement in OS has been noted in cohorts receiving treatments such as tipifarnib. The comutation pattern of HRAS-mutant in HNSCC is distinct, which may provide insight to future therapeutic combination strategies.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Isoprenylation modification required for HIPP1-mediated powdery mildew resistance in wheat. (Pubmed Central) - Nov 3, 2022
Blocking HIPP1-V isoprenylation or tipifarnib treatment reduced such recruitment...In OE-HIPP1-V, the differentially expressed genes of the reactive oxygen species and salicylic acid pathways were remarkable enriched, revealing their involvement in HIPP1-mediated Pm resistance. Our results demonstrated an important defense pathway mediated by protein isoprenylation.
- |||||||||| A SINGLE-INSTITUTION PROPOSAL OF MOLECULAR PROFILING IN ADVANCED SALIVARY GLAND CANCERS: WHY, HOW AND WHEN () - Oct 19, 2022 - Abstract #AIOM2022AIOM_88;
In HG non-ACC, the majority (12/16, 75%) had at least one DNA mutation, of which four druggable (4/12 mutated=33.3%; 4/16 profiled=25%) with tipifarnib, ipatasertib and dabrafenib (D) + trametinib (T) for HRAS (2 cases), AKT and BRAF mutations, respectively. MP of advanced SGCs is suggested, overall in HG tumors of non-ACC cohort, in order to discover fur- ther therapeutics opportunities.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Exosomes form tunneling nanotubes (TUNTs) in the blood-brain barrier: a nano-anatomical perspective of barrier genesis. (Pubmed Central) - Oct 8, 2022
The HR-SEM micrographs in conjunction with the Tipifarnib inhibition of exosome formation, suggests that brain capillary endothelial exosomes play a prominent role in the bilateral signaling, which contribute to the regulation of the permeability of the BBB...These findings could lead to the development of novel treatment interventions and moreover, the characterization of BBB exosomes may be a reliable target for identifying therapeutic biomarkers in neurodegenerative disease. Conversely, the presence of BBB exosomes raises a critical enterprise to target the exosome-induced nanotubes as a vehicle for transferring therapeutic treatments across the BBB.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Targeting HRAS in Head and Neck Cancer: Lessons From the Past and Future Promise. (Pubmed Central) - Sep 29, 2022
Tipifarnib, a farnesyltransferase inhibitor, demonstrated encouraging antitumor activity for HRAS mutant head and neck squamous cell carcinoma and modest activity for HRAS mutant salivary gland cancer. New combination strategies to circumvent intrinsic and acquired resistance to TFIs are being investigated.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Enrollment closed, Enrollment change, Metastases: Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS (clinicaltrials.gov) - Sep 23, 2022
P2, N=9, Active, not recruiting,
[Conclusions] HAVCR2 (TIM3) immunoregulatory factors affect the expression of key genes that affect cytolytic activity in lung adenocarcinoma cells, and to some extent indirectly affect the survival and prognosis of patients with lung adenocarcinoma. Recruiting --> Active, not recruiting | N=18 --> 9
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Iclusig (ponatinib) / Takeda, Otsuka, Incyte, NMI-900 / Nemucore
Biomarker, Journal, IO biomarker: KDELR3 Is a Prognostic Biomarker Related to the Immune Infiltration and Chemoresistance of Anticancer Drugs in Uveal Melanoma. (Pubmed Central) - Sep 10, 2022
The IC50 of AP-24534, BHG712, bleomycin, camptothecin, cisplatin, cytarabine, GSK1070916, and tipifarnib was higher in the KDELR3 high-expression group. In conclusion, KDELR3 may be applied as a potential diagnostic and prognostic biomarker for UM patients.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Mekinist (trametinib) / Novartis
Targeting oncogenic HRAS in pediatric rhabdomyosarcoma (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_305;
Our data suggest that the combination of the FTI tipifarnib and the MEK inhibitor trametinib is active in models of HRAS-driven FN-RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with FN-RMS. No
- |||||||||| Piqray (alpelisib) / Novartis, Zarnestra (tipifarnib) / Kura Oncology
HNSCCs overexpressing wild-type HRAS are sensitive to combined tipifarnib and alpelisib treatment (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_300;
P1/2
Nearly half of HSNCC tumors harbor genomic alterations that suggest dependence on dysregulation of HRAS-MAPK and PI3K-AKT-mTOR pathways. Preclinical data point to a mechanistic synergy between tipifarnib and alpelisib in PIK3CA- and HRAS-dysregulated HNSCC that may overcome the lack of efficacy observed in monotherapy trials with these agents.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Using Tipifarnib to prevent resistance to targeted therapies in oncogene-addicted tumors (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_292;
Similar to what was observed in EGFR-TKi-treated NSCLC, some cells, referred to as "early escapers", could escape G1 and progress through S/G2 during the initial response phase, progressively giving rise to resistant proliferative clones. Co-treatment with tipifarnib prevented relapse in all the models tested by impairing mitosis of S/G2 early escapers and promoting apoptosis.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Preclinical, Journal: The Effect of KRAS on Proliferation and Apoptosis of T-ALL Cell Lines (Pubmed Central) - Aug 28, 2022
Co-treatment with tipifarnib prevented relapse in all the models tested by impairing mitosis of S/G2 early escapers and promoting apoptosis. The KRAS protein is vital for the progression of the T-ALL cells in vitro, it is a potential therapeutic target for T-ALL patients.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Trial completion date, Trial primary completion date, Metastases: Cardiovascular Safety Study of Tipifarnib in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - Aug 18, 2022
P1, N=20, Recruiting,
The novel established FARG signature based on a comprehensive FGFR3 alteration-related transcriptomic profile performed well in prognosis prediction and was also correlated with immunotherapy and chemotherapy treatment responses, which had great potential in future clinical applications. Trial completion date: May 2022 --> May 2023 | Trial primary completion date: May 2022 --> May 2023
- |||||||||| Zokinvy (lonafarnib) / Eiger
Repurposing Screen Identifies lonafarnib as RSV Fusion Protein Inhibitor (Hall 1A) - Aug 1, 2022 - Abstract #ISIRVRSV2022ISIRV_RSV_66;
Oral administration of lonafarnib modestly reduced RSV virus load in a murine infection model. Conclusion Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide F protein inhibitor.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations. (Pubmed Central) - Jul 18, 2022
P2
Conclusion Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide F protein inhibitor. Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist (NCT02383927).
- |||||||||| Biomarker, Journal: Integrative pharmacogenomics revealed three subtypes with different immune landscapes and specific therapeutic responses in lung adenocarcinoma. (Pubmed Central) - Jul 15, 2022
Finally, our study provided subtype-guided personalized treatment strategies: Immune checkpoint blockers (ICBs), doxorubicin, tipifarnib, AZ628, and AZD6244 were for S-Ⅰ; Cisplatin, camptothecin, roscovitine, and A.443654 were for S-Ⅱ; Docetaxel, paclitaxel, vinorelbine, and BIBW2992 were for S-III. We provided a novel molecular classification strategy and revealed three pharmacogenomics-based subtypes for LUAD patients, which uncovered potential subtype-related and patient-specific therapeutic strategies.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Tipifarnib Mediated Protection By Reduction Of Circulating Exosomes In Pressure Overloaded Cardiac Hypertrophy (Salon B, Lower Level) - Jun 18, 2022 - Abstract #BCVS2022BCVS_226;
There was a marked reduction in inflammatory cytokines in serum and differentially expressed exosomal miRNAs with Tipifarnib treatment in comparison to the untreated TAC mice. Overall, our studies suggest the promising potential of Tipifarnib that effectively protects against pressure overload-induced cardiac remodeling and dysfunction by suppressing exosome secretion and altering hypertrophic and fibrotic gene expression.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma. (Pubmed Central) - May 26, 2022
In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of RMS patients.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Molecular characteristics and clinical outcomes of breast cancer with HRAS mutations. (Available On Demand; 333) - Apr 28, 2022 - Abstract #ASCO2022ASCO_3259;
The association of Q61 HRASmut with worse survival highlights the oncogenic role of these mutations and supports therapeutic investigation using FTI. PIK3CA was significantly co-mutated in HRASmut, highlighting a potential benefit of combining PIK3CA inhibitors with tipifarnib.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Sutent (sunitinib) / Pfizer
PD-L1 localization within Exosomes: A Pre-Clinical Study on Exosome Targeting Therapies to Combat Drug Resistance in Renal Cell Carcinoma (Room 244) - Apr 10, 2022 - Abstract #AUA2022AUA_2523;
Source of Funding : None Introduction : TKIs have showed exciting efficacy to treat renal cell carcinoma (RCC), with 70% of patients responding well to initial sunitinib (Suni) dosing...This study sought develop a combination therapy of Tipifarnib (Tipi) + Suni to target exosome conferred drug resistance...Our data shows that exosomes play a pivotal role within the survival of RCC through PD-L1 expression. Using Tipi to block exosome biogenesis, this study demonstrates that Tipi's exosome targeted effects can be implemented with standard therapy to decrease tumor burden.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Drug targeting opportunities en route to Ras nanoclusters. (Pubmed Central) - Mar 31, 2022
Disruption of the native membrane organization of Ras by the farnesyltransferase inhibitor tipifarnib in the late 1990s constituted the first indirect approach to drug target Ras...We highlight drug targeting approaches and opportunities against these determinants of functional Ras membrane organization. Finally, we reflect on implications for Ras signaling in polarized cells, such as epithelia, which are a common origin of tumorigenesis.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Ibrance (palbociclib) / Pfizer, Gilotrif (afatinib) / Boehringer Ingelheim
Clinical, Review, Journal, Tumor Mutational Burden, PD(L)-1 Biomarker, IO biomarker: Genomic Alterations in Head and Neck Squamous Cell Carcinoma: Level of Evidence According to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). (Pubmed Central) - Mar 29, 2022
Molecular alterations in several genes, including PIK3CA gene, were ranked in tier IIIA because of clinical benefit in other tumor types, whereas molecular alterations in IGF1R and TP53 genes were ranked in tier IVA and tier V, respectively. The most compelling actionable molecular alterations in HNSCC according to ESCAT include HRAS-activating mutations, MSI, high TMB, NTRK fusions, CDKN2A-inactivating alterations, and EGFR amplification.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Unituxin (dinutuximab) / United Therapeutics Corp
Tipifarnib inhibits the secretion of tumor-derived small extracellular vesicles and enhances the immunotherapeutic efficacy of dinutuximab in neuroblastoma (Section 37) - Mar 9, 2022 - Abstract #AACR2022AACR_6092;
Notably, Tipifarnib modulated immature myeloid cells in the bone marrow to disfavor the formation of CD11b+Ly6ChighLy6Glow subpopulations, which are the precursors for TAMs. Taken together, these preclinical findings uncover a novel mechanism by which neuroblastoma-derived sEVs modulate the immune system to promote resistance to Dinutuximab and suggest that Tipifarnib-mediated inhibition of sEV secretion may serve as a viable treatment strategy to improve immunotherapy in high-risk patients.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Tipifarnib potentiates the antitumor effects of PI3Ka blockade in HNSCC via convergent inhibition of mTOR activity (Section 24) - Mar 9, 2022 - Abstract #AACR2022AACR_3269;
P1/2
This dual effect implies that the efficacy of tipifarnib in this context may stem from simultaneous defarnesylation of multiple targets, likely HRAS and RHEB, which converge upon mTOR and synergize with alpelisib to durably block tumor growth. We contend that combination of alpelisib and tipifarnib holds therapeutic potential for treatment of recurrent/metastatic HNSCCs harboring dysregulated PIK3CA, which will be evaluated in the recently initiated KURRENT clinical trial (NCT04997902).
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