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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 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 -
Frontiers in Oncology 2023A subgroup of salivary duct carcinoma (SDC) harbor overexpression of the androgen receptor (AR), and co-occurring mutations in the - and -genes. The impact of genomic...
BACKGROUND AND PURPOSE
A subgroup of salivary duct carcinoma (SDC) harbor overexpression of the androgen receptor (AR), and co-occurring mutations in the - and -genes. The impact of genomic complexity on targeted treatment strategies in advanced cancer is unknown.
MATERIALS AND METHODS
We analyzed molecular and clinical data from an institutional molecular tumor board (MTB) to identify AR+, / co-mutated SDC. Follow-up was performed within the MTB registrational study or retrospective chart review after approval by the local ethics committee. Response was assessed by the investigator. A systematic literature search was performed in MEDLINE to identify additional clinically annotated cases.
RESULTS
4 patients with AR+ / co-mutated SDC and clinical follow-up data were identified from the MTB. An additional 9 patients with clinical follow-up were identified from the literature. In addition to AR overexpression and and -alterations, PD-L1 expression and Tumor Mutational Burden > 10 Mutations per Megabase were identified as additional potentially targetable alterations. Among evaluable patients, androgen deprivation therapy (ADT) was initiated in 7 patients (1 Partial Response (PR), 2 Stable Disease (SD), 3 Progressive Disease (PD), 2 not evaluable), tipifarnib was initiated in 6 patients (1 PR, 4 SD, 1 PD). One patient each was treated with immune checkpoint inhibition (Mixed Response) and combination therapies of tipifarnib and ADT (SD) and alpelisib and ADT (PR).
CONCLUSION
Available data further support comprehensive molecular profiling of SDC. Combination therapies, PI3K-inhibitors and immune therapy warrant further investigation, ideally in clinical trials. Future research should consider this rare subgroup of SDC.
PubMed: 37427101
DOI: 10.3389/fonc.2023.1107134 -
International Journal of Molecular... Jul 2023Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But,...
Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But, there are no therapies for NASH-related HCC, especially focusing on these critical steps. Previous studies have reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In hepatoblastoma and HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed the expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed the expression of phosphorylated nuclear factor-κB and transforming growth factor-β. 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.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Liver Neoplasms; Farnesyltranstransferase; Interleukin-6; Hypoxia-Inducible Factor 1, alpha Subunit; Enzyme Inhibitors; Anti-Inflammatory Agents; Inflammation; Cell Line, Tumor
PubMed: 37511305
DOI: 10.3390/ijms241411546 -
European Journal of Cancer (Oxford,... Jun 2023Key molecular alterations (MA) of neuroendocrine neoplasm (NEN) of various grade/primaries have been described but the applicability of molecular profiling (MP) for...
BACKGROUND
Key molecular alterations (MA) of neuroendocrine neoplasm (NEN) of various grade/primaries have been described but the applicability of molecular profiling (MP) for precision medicine in NEN remains to be demonstrated.
METHODS
We conducted a retrospective study of all patients with metastatic NEN who had MP on tumour tissue at Gustave Roussy. The primary objective was to assess the clinical applicability of MP by evaluating the growth modulator index (GMI) as the primary end-point.
RESULTS
MPs were obtained in 114 out of 156 eligible patients, including 12% NET-G1, 42% NET-G2, 13% NET-G3 and 35% neuroendocrine carcinoma (NEC). Primary sites were lung/thymus (40%), pancreas (19%), gastro-intestinal (16%), head&neck (10%), unknown (10%) and others (10%) with synchronous metastases in 61% of the patients. Most frequent MA were: MEN1 (25%), PTEN (13%), TP53 (11%) and TSC2 (9%), in neuroendocrine tumour (NET), and TP53 (50%) and RB1 (18%) in NEC. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) classification of these MA were: I(5%), III(20%), IV(23%), X(27%); a putative actionable MA was identified in 48% patients. Median TMB was 5.7 Mut/Mb, with 3 TMB > 10 and 1 MSI NET. No MA was found in 26% patients. Molecularly matched treatment was administered to 19 patients (4 NEC, 15 NET): immunotherapy (n = 3), tipifarnib (n = 1), NOTCHi (n = 1), EGFRi (n = 2), HER2i (n = 1) and everolimus (n = 11). Overall, 67% of patients had a clinical benefit defined as a GMI over 1.3 with a 78% disease control rate.
CONCLUSION
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.
Topics: Humans; Prognosis; Retrospective Studies; Precision Medicine; Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Pancreatic Neoplasms
PubMed: 37062210
DOI: 10.1016/j.ejca.2023.03.024 -
International Journal of General... 2023associated protein 1 () is shown to regulate cell proliferation and cancer progression. However, the immune-infiltrating correlation and the therapeutics guidance of...
BACKGROUND
associated protein 1 () is shown to regulate cell proliferation and cancer progression. However, the immune-infiltrating correlation and the therapeutics guidance of in hepatocellular carcinoma (HCC) still need further investigation.
METHODS
In this study, comprehensive bioinformatic analysis of on differential expression, clinicopathologic correlation, prognostic value, and function enrichment were performed in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO; GSE14520 and GSE76427), and International Cancer Genome Consortium (ICGC) datasets. Besides, the Guangxi cohort containing 50 pairs HCC and adjacent non-cancerous samples from First Affiliated Hospital of Guangxi Medical University was served as validation cohort. Moreover, we explored the predictive value of to therapeutics response and its underlying correlation with HCC immunoinfiltration.
RESULTS
was significantly overexpressed in HCC tissues and had a high diagnostic value of HCC. The shorter survival time and poorer clinical features were showed when upregulated, and then a nomogram featuring expression and other clinicopathologic factors was established to predict prognosis. In CIBERSORT analysis, higher T cells follicular helper but lower T cells CD4+ memory resting infiltration levels were exhibited when upregulated. The ssGSEA analysis demonstrated that high- expression subgroup had higher macrophages, Th2 and Treg cells infiltration levels, but lower type II IFN response function. Furthermore, high- expression subgroup exhibited the upregulated expression levels of immune-related checkpoint genes, but lower IPS and TIDE scores which suggested a possibly better immunotherapy response. The drug sensitivity analysis showed the high-expression subgroup may be more susceptible to Bexarotene, Doxorubicin, Gemcitabine and Tipifarnib.
CONCLUSION
Taken together, is a potential diagnostic and prognostic biomarker. It may be related to the immunosuppressive microenvironment and could be an underlying HCC treatment strategy. However, the conclusions still require further validation studies.
PubMed: 37789880
DOI: 10.2147/IJGM.S431206 -
Scientific Reports Sep 2023PANoptosis, an interplay between pyroptosis, apoptosis, and necroptosis, is deeply involved in cancer development and immunity. However, the influence of PANoptosis in...
PANoptosis, an interplay between pyroptosis, apoptosis, and necroptosis, is deeply involved in cancer development and immunity. However, the influence of PANoptosis in hepatocellular carcinoma (HCC) remains to be further investigated. The differentially expressed PANoptosis-related genes (PANRGs) was screened in The Cancer Genome Atlas (TCGA) database. Accordingly, mutation, bioinformatics, and consensus clustering analyses were performed. Then, a prognostic risk model was developed by least absolute shrinkage and selection operator (LASSO) Cox regression. Furthermore, the prognostic value, immunity correlation and therapeutic response prediction ability of risk model were explored. A total of 18 PANRGs were differently expressed in the TCGA-HCC cohort and were mainly involved in cancer- and cell death-related signal pathways. Using unsupervised clustering method, we identified two PANRGs-mediated clustering patterns. The remarkable differences between the two clusters on overall survival (OS) and clinical features were demonstrated respectively. Based on the five-gene prognostic risk model, the calculated PANRG-scores were used to categorize the subgroups as high- and low-risk. Notably, the high-risk subgroup had a dismal prognosis and exhibited much lower immune infiltration levels of mast cells, nature killer cells and pDCs, but higher levels of aDCs, iDCs and Treg cells than those in the low-risk subgroup. Furthermore, we constructed a reliable nomogram combining clinical traits and PANRG-score to predict the OS of HCC patients. The significantly negative correlation between PANoptosis and tumor mutation burden (TMB), ferroptosis were revealed. 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 upregulated mRNA expressions of FADD were validated in 16 paired HCC tissues of Guangxi cohort. Based on PANoptosis-related genes, an integrated risk signature was constructed to provide a roadmap for patient stratification and predict HCC patient's prognosis. 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.
Topics: Humans; Carcinoma, Hepatocellular; Prognosis; Liver Neoplasms; China; Nomograms
PubMed: 37666920
DOI: 10.1038/s41598-023-41670-9 -
IScience Jan 2024Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an resistance assay (ISRA) that reliably...
Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an resistance assay (ISRA) that reliably models acquired resistance to RTK/RAS-pathway-targeted therapies across cell lines. Using osimertinib resistance in -mutated lung adenocarcinoma (LUAD) as a model system, we show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using SHP2 inhibitors. Isolated osimertinib-resistant populations required SHP2 inhibition to resensitize cells to osimertinib and reduce MAPK signaling to block the effects of enhanced activation of multiple parallel RTKs. We additionally modeled resistance to targeted therapies including the KRAS inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.
PubMed: 38226159
DOI: 10.1016/j.isci.2023.108711 -
British Journal of Cancer Apr 2024Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer....
BACKGROUND
Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors.
METHODS
Combinations of clinically approved farnesyl-transferase inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung adenocarcinoma. Treatment effects on migration, proliferation, apoptosis, farnesylation and RAS signaling were measured by histopathological analyses, videomicroscopy, cell cycle analyses, immunoblot, immunofluorescence and RAS pulldown.
RESULTS
Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS G1C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models.
DISCUSSION
Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.
Topics: Humans; Animals; Adenocarcinoma; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Adenocarcinoma of Lung; Lung Neoplasms; Disease Models, Animal; Enzyme Inhibitors; Transferases; Colorectal Neoplasms; Mutation
PubMed: 38278976
DOI: 10.1038/s41416-024-02586-x -
Research Square Jul 2023The clinical development of farnesyltransferase inhibitors (FTI) for -mutant tumors showed mixed responses dependent on cancer type. Co-occurring mutations may affect...
The clinical development of farnesyltransferase inhibitors (FTI) for -mutant tumors showed mixed responses dependent on cancer type. Co-occurring mutations may affect response. We aimed to uncover cooperative genetic events specific to -mutant tumors and study their effect on FTI sensitivity. Using targeted sequencing data from MSK-IMPACT and DFCI-GENIE databases we identified co-mutations in - vs - and -mutant cancers. -mutant cancers had a higher frequency of co-altered mutations (48.8%) in MAPK, PI3K, or RTK pathways genes compared to - and -mutant cancers (41.4% and 38.4%, respectively; p < 0.05). Class 3 mutations were more prevalent in -mutant lineages. To study the effect of comutations on FTI sensitivity, was transfected into 'RASless' (;;) mouse embryonic fibroblasts (MEFs) which sensitized non-transfected MEFs to tipifarnib. Comutation in the form of or deletion or or transduction led to relative resistance to tipifarnib in MEFs in the presence or absence of Kras. Combined treatment of tipifarnib with MEK inhibition sensitized cells to tipifarnib, including in MEFs with PI3K pathway comutations. -mutant tumors demonstrate lineage demonstrate lineage-dependent MAPK/PI3K pathway alterations that confer relative resistance to tipifarnib. Combined FTI and MEK inhibition is a promising combination for -mutant tumors.
PubMed: 37503077
DOI: 10.21203/rs.3.rs-3154719/v1