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Clinical, Review, Journal: Risk-Adapted, Individualized Treatment Strategies of Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). (Pubmed Central) - Apr 7, 2021 Although early results from novel molecularly driven agents such as IDH1/2 inhibitors, venetoclax, magrolimab, and APR-246 for MDS as well as tagraxofusp, tipifarnib, and lenzilumab for CMML appear encouraging, confirmatory randomized trials must be completed to fully assess their safety and efficacy prior to routine clinical use. Herein, we review the current management of MDS and CMML and conclude with a critical appraisal of novel therapies and general trends in this field.
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Clinical, Journal: A Farnesyltransferase Inhibitor Shows Efficacy in HRAS-Mutant HNSCC. (Pubmed Central) - Apr 7, 2021 Herein, we review the current management of MDS and CMML and conclude with a critical appraisal of novel therapies and general trends in this field. Tipifarnib produced responses in patients with head-and-neck squamous-cell carcinoma (HNSCC).
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[VIRTUAL] Mechanisms of Therapeutic Response to Tipifarnib in a Mouse Model of Angioimmunoblastic T-Cell Lymphoma (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_3805; CYBERSORT analysis of hematopoietic cell populations indicated that treatment with tipifarnib in our mouse lymphoma model is associated with enrichment in NK signatures and a potential decrease of monocytes and neutrophils within the tumor microenvironment. In summary, we have demonstrated that tipifarnib has a strong anti-lymphoma effect on a mouse model of AITL and that this effect might be mediated by the recruitment and/or activation of different hematopoietic cell populations in the tumor microenvironment that can alter the survival and proliferation of lymphoma cells.
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[VIRTUAL] Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated head and neck squamous cell carcinoma () - Sep 7, 2020 - Abstract #AACRNCIEORTC2020AACR_NCI_EORTC_284; P2 Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or with PIK3CAmutations or amplification and in HRAS mutants that carried or lacked PIK3CA mutations, suggesting concomitant blockade of both targets may have broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will be reported.
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[VIRTUAL] Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated head and neck squamous cell carcinoma () - Sep 7, 2020 - Abstract #AACRNCIEORTC2020AACR_NCI_EORTC_283; P2 Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or with PIK3CAmutations or amplification and in HRAS mutants that carried or lacked PIK3CA mutations, suggesting concomitant blockade of both targets may have broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will be reported.
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Journal: Design, Synthesis and Biological Evaluation of Novel Piperazinone Derivatives as Cytotoxic Agents. (Pubmed Central) - Jul 17, 2020 Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will be reported. In this study, a series of piperazin-2-one derivatives were prepared through bioisosteric substitution of the imidazole ring of L-778,123 (imidazole-containing FTase inhibitor) and rearrangement of groups based on the tipifarnib structure...It seems the electron density of substituted groups and rearrangement of groups may significantly increase cytotoxic activity.
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Biomarker, Enrollment open, Trial initiation date, Metastases: Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial (clinicaltrials.gov) - Jul 14, 2020 P2, N=49, Recruiting, In this study, a series of piperazin-2-one derivatives were prepared through bioisosteric substitution of the imidazole ring of L-778,123 (imidazole-containing FTase inhibitor) and rearrangement of groups based on the tipifarnib structure...It seems the electron density of substituted groups and rearrangement of groups may significantly increase cytotoxic activity. Not yet recruiting --> Recruiting | Initiation date: Oct 2020 --> Jul 2020
- |||||||||| Review, Journal: Chronic Myelomonocytic Leukemia: 2018 Update to Prognosis and Treatment. (Pubmed Central) - Jul 4, 2020
Increased recognition and interest in CMML have led to the development of a number of new prognostic models and potential treatment options. Standard treatment options remain limited and clinical trials should be strongly considered whenever available.
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Journal: The farnesyltransferase β-subunit RAM1 regulates localization of RAS proteins and appressorium-mediated infection in Magnaporthe oryzae. (Pubmed Central) - Jun 26, 2020 Adding a farnesyltransferase inhibitor Tipifarnib can result in similar defects as in Δram1 mutant, including decreased appressorium formation and invasive growth, as well as mislocalized RAS proteins. Our findings indicate that protein farnesylation regulates the RAS protein-mediated signaling pathways required for appressorium formation and host infection, and suggest that abolishing farnesyltransferase could be an effective strategy for disease control.
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Enrollment closed, Enrollment change, Trial completion date: Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia, Other MDS/MPN, and Acute Myeloid Leukemia (clinicaltrials.gov) - Jun 23, 2020 P2, N=45, Active, not recruiting, Our findings indicate that protein farnesylation regulates the RAS protein-mediated signaling pathways required for appressorium formation and host infection, and suggest that abolishing farnesyltransferase could be an effective strategy for disease control. Recruiting --> Active, not recruiting | N=72 --> 45 | Trial completion date: May 2022 --> May 2021
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Enrollment closed, Trial completion date, Trial primary completion date, Metastases: KO-TIP-001: Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations (clinicaltrials.gov) - Jun 23, 2020 P2, N=63, Active, not recruiting, Recruiting --> Active, not recruiting | N=30 --> 65 Recruiting --> Active, not recruiting | Trial completion date: Oct 2020 --> May 2021 | Trial primary completion date: Mar 2020 --> Jan 2021
- |||||||||| Biomarker, Enrollment change, BRCA Biomarker, PARP Biomarker, Metastases: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - Apr 1, 2020
P2, N=1500, Recruiting, Initiation date: Mar 2020 --> Sep 2020 N=1000 --> 1500
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