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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 -
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 -
Pediatric Blood & Cancer Feb 2011The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib,...
Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group.
BACKGROUND
The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies.
PROCEDURE
Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m(2) /dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity.
RESULTS
Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m(2) /dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 ml/min/m(2) and the median half-life was 4.7 hr. At steady state on 300 mg/m(2) /dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed.
CONCLUSIONS
Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 2 days schedule at 300 mg/m(2) /dose.
Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Farnesyltranstransferase; Female; Half-Life; Humans; Infant; Leukemia; Male; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Quinolones
PubMed: 20860038
DOI: 10.1002/pbc.22775 -
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 -
Leukemia Research Feb 2015There is no standard of care for older patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive therapy, and prognosis with currently recommended... (Review)
Review
There is no standard of care for older patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive therapy, and prognosis with currently recommended low-intensity therapies (decitabine, azacitidine, and low-dose cytarabine [LDAC]) remains poor. One promising strategy is to combine low-intensity treatments with novel agents. Gemtuzumab ozogamicin, tipifarnib, and barasertib have been investigated in phase 2/3 or 3 trials combined with LDAC, and phase 3 trials are currently investigating sapacitabine plus decitabine, and volasertib plus LDAC in AML. This review discusses current treatment recommendations and the development of combination therapies for older patients unfit for intensive therapy.
Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Critical Care; Cytarabine; Decitabine; Female; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Male; Organophosphates; Quinazolines; Quinolones
PubMed: 25577399
DOI: 10.1016/j.leukres.2014.11.027 -
Cancer Sep 2020To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant... (Clinical Trial)
Clinical Trial
BACKGROUND
To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC.
METHODS
The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.
RESULTS
A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.
CONCLUSIONS
Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Progression-Free Survival; Proto-Oncogene Proteins p21(ras); Quinolones; Salivary Gland Neoplasms; Treatment Outcome
PubMed: 32557577
DOI: 10.1002/cncr.33036 -
Cancer Mar 2011The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia...
A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome.
BACKGROUND
The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome.
METHODS
Induction consisted of idarubicin 12 mg/m(2) a day on days 1-3, cytarabine 1.5 g/m(2) intravenously continuously daily on days 1-4 (days 1-3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m(2) a day on days 1-2, cytarabine 0.75 g/m(2) a day on days 1-3, and tipifarnib 300 mg twice a day for 14 days every 4-6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4-6 weeks was continued for 6 months.
RESULTS
With a median follow-up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities.
CONCLUSIONS
The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor-risk AML.
Topics: Adolescent; Adult; Age of Onset; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Idarubicin; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Neoadjuvant Therapy; Neoplasm Staging; Quinolones; Remission Induction; Risk; Young Adult
PubMed: 20960519
DOI: 10.1002/cncr.25575 -
Frontiers in Cellular and Infection... 2019The protozoan parasite can induce amebic colitis and amebic liver abscess. First-line drugs for the treatment of amebiasis are nitroimidazoles, particularly...
The protozoan parasite can induce amebic colitis and amebic liver abscess. First-line drugs for the treatment of amebiasis are nitroimidazoles, particularly metronidazole. Metronidazole has side effects and potential drug resistance is a concern. Schistosomiasis, a chronic and painful infection, is caused by various species of the flatworm. There is only one partially effective drug, praziquantel, a worrisome situation should drug resistance emerge. As many essential metabolic pathways and enzymes are shared between eukaryotic organisms, it is possible to conceive of small molecule interventions that target more than one organism or target, particularly when chemical matter is already available. Farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway, is vital for diverse functions, including cell differentiation and growth. Both and genomes encode FT genes. In this study, we phenotypically screened and with the established FT inhibitors, lonafarnib and tipifarnib, and with 125 tipifarnib analogs previously screened against both the whole organism and/or the FT of and . For , we also explored whether synergy arises by combining lonafarnib and metronidazole or lonafarnib with statins that modulate protein prenylation. We demonstrate the anti-amebic and anti-schistosomal activities of lonafarnib and tipifarnib, and identify 17 tipifarnib analogs with more than 75% growth inhibition at 50 μM against . Apart from five analogs of tipifarnib exhibiting activity against both and , 10 additional analogs demonstrated anti-schistosomal activity (severe degenerative changes at 10 μM after 24 h). Analysis of the structure-activity relationship available for the FT suggests that FT may not be the relevant target in and . For , combination of metronidazole and lonafarnib resulted in synergism for growth inhibition. Also, of a number of statins tested, simvastatin exhibited moderate anti-amebic activity which, when combined with lonafarnib, resulted in slight synergism. Even in the absence of a definitive molecular target, identification of potent anti-parasitic tipifarnib analogs encourages further exploration while the synergistic combination of metronidazole and lonafarnib offers a promising treatment strategy for amebiasis.
Topics: Amebiasis; Animals; Biomphalaria; Cell Survival; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy; Entamoeba histolytica; Farnesyltranstransferase; Female; Metronidazole; Piperidines; Pyridines; Quinolones; Schistosoma mansoni; Trypanosoma brucei brucei; Trypanosoma cruzi
PubMed: 31192168
DOI: 10.3389/fcimb.2019.00180 -
International Journal of Molecular... Jan 2023Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy,...
Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the clinical progression of OSCC and its responsiveness to therapy is strongly required. To meet this need, here we have employed Whole Genome Sequencing and RNA-seq data from a cohort of 316 patients retrieved from the TCGA Pan-Cancer Atlas to analyze the genomic and transcriptomic status of the DNA damage response (DDR) genes in OSCC. Then, we correlated the transcriptomic data with the clinical parameters of each patient. Finally, we relied on transcriptomic and drug sensitivity data from the CTRP v2 portal, performing Pearson's correlation analysis to identify putative vulnerabilities of OSCC cell lines correlated with DDR gene expression. Our results indicate that several DDR genes show a high frequency of genomic and transcriptomic alterations and that the expression of some of them correlates with OSCC grading and infection by the human papilloma virus. In addition, we have identified a signature of eight DDR genes (namely , , , , , , , and ) that could be predictive for OSCC response to the novel antitumor compounds sorafenib and tipifarnib-P1. Altogether, our data demonstrate that alterations in DDR genes could have an impact on the biology of OSCC. Moreover, here we propose a DDR gene signature whose expression could be predictive of OSCC responsiveness to therapy.
Topics: Humans; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Mouth Neoplasms; DNA Damage; Head and Neck Neoplasms
PubMed: 36768994
DOI: 10.3390/ijms24032673 -
Cancer Control : Journal of the Moffitt... Apr 2007Clonal diseases of large granular lymphocytes (LGLs) are rare lymphoproliferative malignancies that arise from either mature T-cell (CD3+) or natural killer (NK)-cell... (Review)
Review
BACKGROUND
Clonal diseases of large granular lymphocytes (LGLs) are rare lymphoproliferative malignancies that arise from either mature T-cell (CD3+) or natural killer (NK)-cell (CD3-) lineages. They manifest a distinct biologic behavior that ranges from indolent to very aggressive.
METHODS
We discuss four distinct diseases involving LGLs: indolent T-cell LGL leukemia, aggressive T-cell LGL leukemia, chronic NK-cell leukemia, and aggressive NK-cell leukemia. Furthermore, we present an up-to-date systematic review of therapies for each entity.
RESULTS
Sustained LGLs, characteristic immunophenotype, clonal origin of leukemic cells, and clinical presentation are the most important features that distinguish indolent from aggressive subtypes of LGL leukemia and guide the selection of therapy. Patients with symptomatic indolent T-cell or NK-cell LGL leukemia are usually treated with immunosuppressive therapies in contrast to aggressive T-cell and NK-cell LGL leukemia, which require intensive chemotherapy induction regimens. Novel targeted therapies using monoclonal antibodies against receptors, including CD2, CD52, the beta subunit of the interleukin-2 receptor, and small molecules such as tipifarnib, are undergoing evaluation in clinical trials.
CONCLUSIONS
Future scientific advances focusing on the delineation of molecular pathogenic mechanisms and the development of new targeted therapies for each distinct LGL leukemia entity should lead to improved outcomes of patients with these disorders.
Topics: CD3 Complex; Humans; Killer Cells, Natural; Leukemia, Lymphoid; Leukemia, T-Cell; Lymphocytes
PubMed: 17387299
DOI: 10.1177/107327480701400207