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Journal of Clinical Oncology : Official... Jun 2021Mutations in the (m) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a...
PURPOSE
Mutations in the (m) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts function. We evaluated the efficacy of tipifarnib in patients with R/M m HNSCC.
METHODS
We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m variant allele frequency (VAF) data, enrollment was limited to those with a m VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.
RESULTS
Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).
CONCLUSION
Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with mutations for whom limited therapeutic options exist (NCT02383927).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mutation, Missense; Proto-Oncogene Mas; Proto-Oncogene Proteins p21(ras); Quinolones; Squamous Cell Carcinoma of Head and Neck; Young Adult
PubMed: 33750196
DOI: 10.1200/JCO.20.02903 -
Genome Medicine May 2020Tumor cell-intrinsic mechanisms and complex interactions with the tumor microenvironment contribute to therapeutic failure via tumor evolution. It may be possible to...
Single-cell RNA sequencing reveals the tumor microenvironment and facilitates strategic choices to circumvent treatment failure in a chemorefractory bladder cancer patient.
BACKGROUND
Tumor cell-intrinsic mechanisms and complex interactions with the tumor microenvironment contribute to therapeutic failure via tumor evolution. It may be possible to overcome treatment resistance by developing a personalized approach against relapsing cancers based on a comprehensive analysis of cell type-specific transcriptomic changes over the clinical course of the disease using single-cell RNA sequencing (scRNA-seq).
METHODS
Here, we used scRNA-seq to depict the tumor landscape of a single case of chemo-resistant metastatic, muscle-invasive urothelial bladder cancer (MIUBC) addicted to an activating Harvey rat sarcoma viral oncogene homolog (HRAS) mutation. In order to analyze tumor evolution and microenvironmental changes upon treatment, we also applied scRNA-seq to the corresponding patient-derived xenograft (PDX) before and after treatment with tipifarnib, a HRAS-targeting agent under clinical evaluation.
RESULTS
In the parallel analysis of the human MIUBC and the PDX, diverse stromal and immune cell populations recapitulated the cellular composition in the human and mouse tumor microenvironment. Treatment with tipifarnib showed dramatic anticancer effects but was unable to achieve a complete response. Importantly, the comparative scRNA-seq analysis between pre- and post-tipifarnib-treated PDX revealed the nature of tipifarnib-refractory tumor cells and the tumor-supporting microenvironment. Based on the upregulation of programmed death-ligand 1 (PD-L1) in surviving tumor cells, and the accumulation of multiple immune-suppressive subsets from post-tipifarnib-treated PDX, a PD-L1 inhibitor, atezolizumab, was clinically applied; this resulted in a favorable response from the patient with acquired resistance to tipifarnib.
CONCLUSION
We presented a single case report demonstrating the power of scRNA-seq for visualizing the tumor microenvironment and identifying molecular and cellular therapeutic targets in a treatment-refractory cancer patient.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Male; Mice; Middle Aged; Proto-Oncogene Proteins p21(ras); Quinolones; RNA-Seq; Single-Cell Analysis; Transcriptome; Treatment Failure; Tumor Microenvironment; Urinary Bladder Neoplasms
PubMed: 32460812
DOI: 10.1186/s13073-020-00741-6 -
Nature Communications Jun 2022The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient...
The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.
Topics: Bone Neoplasms; Genomics; Humans; Osteosarcoma; Sarcoma; Soft Tissue Neoplasms
PubMed: 35705560
DOI: 10.1038/s41467-022-30453-x -
Cancer Research Oct 2023Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18...
UNLABELLED
Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.
SIGNIFICANCE
The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Neoplasm Recurrence, Local; TOR Serine-Threonine Kinases; Head and Neck Neoplasms; Class I Phosphatidylinositol 3-Kinases; Biomarkers; Proto-Oncogene Proteins p21(ras)
PubMed: 37339176
DOI: 10.1158/0008-5472.CAN-23-0282 -
Cancer Research Apr 2023The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS...
UNLABELLED
The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated 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.
SIGNIFICANCE
Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.
Topics: Humans; Proteomics; Transcription Factors; Cell Line, Tumor; Signal Transduction; Head and Neck Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 36753744
DOI: 10.1158/0008-5472.CAN-22-2586 -
Oncogene May 2022Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been...
Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. 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 patients with RMS.
Topics: Farnesyltranstransferase; Genes, ras; Humans; Prenylation; Proto-Oncogene Proteins p21(ras); Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal
PubMed: 35459782
DOI: 10.1038/s41388-022-02305-x -
Cancer Research Oct 2023Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for...
Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for translational research. 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.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Precision Medicine; Cell Line, Tumor; Head and Neck Neoplasms; TOR Serine-Threonine Kinases; Class I Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins p21(ras)
PubMed: 37779427
DOI: 10.1158/0008-5472.CAN-23-1858 -
Journal of Global Antimicrobial... Mar 2023The emergence of SARS-CoV-2 in 2019 led to a severe pandemic situation. Treatment options are limited, and the efficacy of vaccines decreases due to mutations in...
OBJECTIVES
The emergence of SARS-CoV-2 in 2019 led to a severe pandemic situation. Treatment options are limited, and the efficacy of vaccines decreases due to mutations in SARS-CoV-2 strains. Therefore, new treatment options are urgently needed, and computational compound screenings are used to predict drugs quickly. One of these screenings revealed farnesyltransferase inhibitors (FTIs) as potential candidates.
METHODS
SARS-CoV-2 infected Calu-3 cells were treated with lonafarnib and tipifarnib and fold change viral replication of SARS-CoV-2 was measured using RT-qPCR. Furthermore, morphological changes, like CPE formation, were evaluated. Effects on Calu-3 cells were analyzed using MTT assay.
RESULTS
We demonstrated that the FTIs lonafarnib and tipifarnib have an effect on SARS-CoV-2 Wildtype and the Delta variant. Both FTIs dose-dependently reduced morphological changes and the formation of cytopathic effects in SARS-CoV-2 infected Calu-3 cells. The effect of the FTIs on Omicron needs to be further elucidated because of inefficient viral replication.
CONCLUSIONS
The FTI lonafarnib and tipifarnib might be effective drugs against different SARS-CoV-2 strains.
Topics: Humans; COVID-19; Farnesyltranstransferase; SARS-CoV-2; Enzyme Inhibitors
PubMed: 36462736
DOI: 10.1016/j.jgar.2022.11.011 -
Molecular Cancer Dec 2022Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of...
BACKGROUND
Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of Hippo intermediates only identify a minority of cancers with illegitimate YAP activation. Yap has been implicated in resistance to targeted therapies, but the mechanisms by which YAP may impact adaptive resistance to MAPK inhibitors are unknown.
METHODS
We screened 52 thyroid cancer cell lines for illegitimate nuclear YAP localization by immunofluorescence and fractionation of cell lysates. We engineered a doxycycline (dox)-inducible thyroid-specific mouse model expressing constitutively nuclear YAP, alone or in combination with endogenous expression of either Hras or Braf. We also generated cell lines expressing dox-inducible sh-miR-E-YAP and/or YAP. We used cell viability, invasion assays, immunofluorescence, Western blotting, qRT-PCRs, flow cytometry and cell sorting, high-throughput bulk RNA sequencing and in vivo tumorigenesis to investigate YAP dependency and response of BRAF-mutant cells to vemurafenib.
RESULTS
We found that 27/52 thyroid cancer cell lines had constitutively aberrant YAP nuclear localization when cultured at high density (NU-YAP), which rendered them dependent on YAP for viability, invasiveness and sensitivity to the YAP-TEAD complex inhibitor verteporfin, whereas cells with confluency-driven nuclear exclusion of YAP (CYT-YAP) were not. Treatment of BRAF-mutant thyroid cancer cells with RAF kinase inhibitors resulted in YAP nuclear translocation and activation of its transcriptional output. Resistance to vemurafenib in BRAF-mutant thyroid cells was driven by YAP-dependent NRG1, HER2 and HER3 activation across all isogenic human and mouse thyroid cell lines tested, which was abrogated by silencing YAP and relieved by pan-HER kinase inhibitors. YAP activation induced analogous changes in BRAF melanoma, but not colorectal cells.
CONCLUSIONS
YAP activation in thyroid cancer generates a dependency on this transcription factor. YAP governs adaptive resistance to RAF kinase inhibitors and induces a gene expression program in BRAF-mutant cells encompassing effectors in the NRG1 signaling pathway, which play a central role in the insensitivity to MAPK inhibitors in a lineage-dependent manner. HIPPO pathway inactivation serves as a lineage-dependent rheostat controlling the magnitude of the adaptive relief of feedback responses to MAPK inhibitors in BRAF- cancers.
Topics: Humans; Animals; Mice; Thyroid Neoplasms; raf Kinases
PubMed: 36476495
DOI: 10.1186/s12943-022-01676-9 -
Journal of Hematology & Oncology Jul 2013Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can... (Review)
Review
Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.
Topics: Animals; Antineoplastic Agents; Cytokines; Enzyme Inhibitors; Humans; Myelodysplastic Syndromes; Signal Transduction
PubMed: 23841999
DOI: 10.1186/1756-8722-6-50