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Frontiers in Microbiology 2021Farnesyltransferase inhibitors (FTIs) are focus for the treatment of several diseases, particularly in the field of cancer therapy. Their potential, however, goes even...
Farnesyltransferase inhibitors (FTIs) are focus for the treatment of several diseases, particularly in the field of cancer therapy. Their potential, however, goes even further, as a number of studies have evaluated FTIs for the treatment of infectious diseases such as malaria, African sleeping sickness, leishmaniosis, and hepatitis D virus infection. Little is known about protein prenylation mechanisms in human pathogens. However, disruption of , a gene encoding the geranyltranstransferase of () leads to reprogramming of cellular behavior as well as impaired growth and decreased resistance to cell wall-targeting antibiotics. We used an agar well diffusion assay and a time kill assay and determined the minimum inhibitory concentrations of the FTIs lonafarnib and tipifarnib. Additionally, we conducted cell viability assays. We aimed to characterize the effect of these FTIs on , methicillin-resistant (MRSA), (), (), (), (), (), and (). Both the FTIs lonafarnib and tipifarnib were capable of inhibiting the growth of the Gram-positive bacteria , MRSA, , and , whereas no effect was observed on Gram-negative bacteria. The analysis of the impact of lonafarnib and tipifarnib on common human pathogens might lead to novel insights into their defense mechanisms and therefore provide new therapeutic targets for antibiotic-resistant bacterial infections.
PubMed: 34917041
DOI: 10.3389/fmicb.2021.628283 -
The Journal of Clinical Endocrinology... Apr 2011Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular...
Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies.
PURPOSE
Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins.
PATIENTS AND METHODS
We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle.
RESULTS
We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue.
CONCLUSIONS
Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.
Topics: Adenocarcinoma, Follicular; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Neuroendocrine; Cell Differentiation; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Farnesyltranstransferase; Female; Humans; MAP Kinase Kinase Kinases; Male; Middle Aged; Niacinamide; Oncogene Protein p21(ras); Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyridines; Quinolones; Signal Transduction; Sorafenib; Thyroid Neoplasms; raf Kinases
PubMed: 21289252
DOI: 10.1210/jc.2010-1899 -
The Oncologist Mar 2007As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients.... (Review)
Review
As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients. Bortezomib and tipifarnib are two new, targeted treatments for hematologic malignancies. Bortezomib, a proteasome inhibitor, has shown impressive efficacy in patients with relapsed multiple myeloma and as initial treatment, including before autologous stem cell transplantation. It has been studied as monotherapy and in combination with standard treatments such as dexamethasone, and with newer agents such as the immunomodulators thalidomide and lenalidomide; response is encouraging, even in patients who have relapsed after previously receiving components of a regimen as single agents. Bortezomib is generally well tolerated, including in combination with novel and conventional agents. Tipifarnib is a specific inhibitor of farnesyltransferase. Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib. Continued investigation with these new, targeted treatments will further define their use as treatment options in patients with hematologic cancer.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Hematologic Neoplasms; Humans; Pyrazines; Quinolones
PubMed: 17405892
DOI: 10.1634/theoncologist.12-3-281 -
Current Opinion in Hematology Mar 2009This review focuses on new strategies for unmet clinical needs and on new targeted therapies in classical Philadelphia-negative myeloproliferative neoplasms. (Review)
Review
PURPOSE OF REVIEW
This review focuses on new strategies for unmet clinical needs and on new targeted therapies in classical Philadelphia-negative myeloproliferative neoplasms.
RECENT FINDINGS
Meta-analyses in essential thrombocythemia documented Janus kinase 2 (JAK2) V617F as being associated with increased risk of thrombosis. New studies reinforced the evidence of leukocytosis as an independent risk factor for thrombosis in polycythemia vera and essential thrombocythemia. In a phase II trial of pegylated interferon-alpha2a in polycythemia vera patients, a decrease of JAK2 mutant expression to undetectable levels was demonstrated. New trials documented that 5-azacytidine and bortezomib have negligible effect in primary myelofibrosis, whereas thalidomide and tipifarnib produce 22 and 44% response, respectively. In primary myelofibrosis, the JAK2 inhibitor, INCB018424, resulted in a rapid and marked reduction in splenomegaly and a clinical improvement, with a modest effect on JAK2 V617F burden.
SUMMARY
Treating low-risk essential thrombocythemia and polycythemia vera patients presenting with leukocytosis or JAK2 V617F mutation in order to prevent thrombosis deserves a prospective validation. Pursuing clonal remission in polycythemia vera by interferon needs new evidence. Tipifarnib may be added to conventional therapeutic instruments for symptomatic primary myelofibrosis. The results of anti-JAK2-targeted therapies are encouraging as regards symptoms reduction but not clonal remission.
Topics: Chronic Disease; Humans; Interferon alpha-2; Interferon-alpha; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Quinolones; Recombinant Proteins; Thalidomide
PubMed: 19468275
DOI: 10.1097/MOH.0b013e3283257a9e -
Leukemia Research Dec 2021Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of... (Randomized Controlled Trial)
Randomized Controlled Trial
Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.
PURPOSE
Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse.
PATIENTS AND METHODS
Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients.
RESULTS
One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001).
CONCLUSION
This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.
Topics: Antineoplastic Agents; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Quinolones; Salvage Therapy; Survival Rate
PubMed: 34773794
DOI: 10.1016/j.leukres.2021.106736 -
International Immunopharmacology Jun 2020No effective treatment has been established for autoimmune hepatitis (AIH), except for liver transplantation in the fatal stage. Little is known about the roles and...
No effective treatment has been established for autoimmune hepatitis (AIH), except for liver transplantation in the fatal stage. Little is known about the roles and mechanisms of farnesyltransferase inhibitors (FTIs) in treating AIH. Thus, we investigated the specific role of the FTI, tipifarnib, in a Concanavalin A (Con A)-induced model of hepatitis. The effects of tipifarnib (10 mg/kg, intraperitoneal injection) were studied in Con A (20 mg/kg, intravenous injection)-challenged mice by histological, biochemical, and immunological analyses. Tipifarnib-treated mice were compared to phosphate-buffered saline (PBS)-treated mice. Con A caused liver injury characterized by increased plasma alanine aminotransferase (ALT) levels and marked histological changes. The increased serum ALT, interleukin-6, or interferon-γ (IFN-γ) levels were observed at 2 or 8 h; tumor necrosis factor-α levels at 2 h post-Con A administration decreased significantly in the tipifarnib group. Tipifarnib also suppressed Con A-induced activation of CD4 cells (but not CD8 T cells) in the liver and spleen, and also reversed the Con A-induced decrease of natural killer T (NKT) cells in the liver. Tipifarnib significantly inhibited IFN-γ production and STAT1 phosphorylation from CD4 T cells (but not CD8 T and NKT cells) in the liver at 2 h post-Con A administration. Tipifarnib significantly inhibited IFN-γ production by splenic CD4 T cells at 48 h post-Con A injection in vitro. Tipifarnib also inhibited the expression of farnesylated proteins induced by Con A administration. In conclusion, tipifarnib inhibited IFN-γ derived from Con A-induced CD4 T cell activation due to downregulated STAT1 phosphorylation, suggesting that Tipifarnib can protect against AIH.
Topics: Animals; Antineoplastic Agents; CD4-Positive T-Lymphocytes; Cells, Cultured; Concanavalin A; Disease Models, Animal; Hepatitis, Autoimmune; Humans; Interferon-gamma; Liver; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Quinolones
PubMed: 32251961
DOI: 10.1016/j.intimp.2020.106462 -
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 -
Neuro-oncology Mar 2011We performed a phase II study to assess the efficacy and toxicity of tipifarnib, a farnesyltransferase inhibitor, administered with radiation therapy (RT) in children...
We performed a phase II study to assess the efficacy and toxicity of tipifarnib, a farnesyltransferase inhibitor, administered with radiation therapy (RT) in children with newly diagnosed diffuse intrinsic pontine gliomas. Children 3-21 years old with pontine gliomas (BSGs) were treated with concurrent tipifarnib and RT, followed by adjuvant tipifarnib. Tipifarnib was taken orally twice daily (125 mg/m(2)/dose) during RT; after RT, it was taken at 200 mg/m(2) twice daily for 21 days, in 28-day cycles. Initial and follow-up neuroimaging was centrally reviewed. Forty eligible patients (median age, 5.5 years; range, 3.3-16.5 years) had a median progression-free survival of 6.8 months (range, 0.2-18.6 months) and median overall survival of 8.3 months (range, 0.2-18.6 months). Kaplan-Meier estimates (± standard error) of 1-year progression-free and overall survival were 12.9% ±4.9% and 34.3% ±7.4%, respectively. A single patient remained on tipifarnib without progression at the completion of the study, two years after initiation of treatment. Seven patients were without disease progression for at least six months, three of whom remained controlled for more than a year. The most frequent toxicity was grade 3 lymphopenia. We documented a single instance of "pseudoprogression" by neuroimaging review. We found no discordance among 3 approaches to defining disease progression: as interpreted by treating institutions (based on clinical status and/or imaging) and by central review (using bi-dimensional tumor "area" versus volumetric measurements). For children with diffuse BSGs, tipifarnib administered with irradiation offered no clinical advantage over historical controls. Biopsies and molecular analyses of pediatric BSGs are vital for identification of new agents and for rational use of targeted agents.
Topics: Adolescent; Adult; Antineoplastic Agents; Brain Stem Neoplasms; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Pons; Quinolones; Radiotherapy Dosage; Survival Rate; Tissue Distribution; Treatment Outcome; Young Adult
PubMed: 21339191
DOI: 10.1093/neuonc/noq202 -
Neuro-oncology May 2014RAS is dysregulated in neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs). The activity of tipifarnib, which blocks RAS signaling by inhibiting its... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.
BACKGROUND
RAS is dysregulated in neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs). The activity of tipifarnib, which blocks RAS signaling by inhibiting its farnesylation, was tested in children and young adults with NF1 and progressive PNs.
METHODS
Patients aged 3-25 years with NF1-related PNs and imaging evidence of tumor progression were randomized in a double-blinded fashion to receive tipifarnib (200 mg/m(2) orally every 12 h) or placebo (phase A) and crossed over to the opposite treatment arm at the time of tumor progression (phase B). PN volumes were measured with MRI, and progression was defined as ≥20% volume increase. Time to progression (TTP) in phase A was the primary endpoint, and the trial was powered to detect whether tipifarnib doubled TTP compared with placebo. Toxicity, response, and quality of life were also monitored.
RESULTS
Sixty-two patients were enrolled. Tipifarnib and placebo were well tolerated. On phase A, the median TTP was 10.6 months on the placebo arm and 19.2 months on the tipifarnib arm (P = .12; 1-sided). Quality of life improved significantly compared with baseline on the tipifarnib arm but not on the placebo arm. Volumetric tumor measurement detected tumor progression earlier than conventional 2-dimensional (WHO) and 1-dimensional (RECIST) methods.
CONCLUSIONS
Tipifarnib was well tolerated but did not significantly prolong TTP of PNs compared with placebo. The randomized, flexible crossover design and volumetric PN assessment provided a feasible and efficient means of assessing the efficacy of tipifarnib. The placebo arm serves as an historical control group for phase 2 single-arm trials directed at progressive PNs.
Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Cross-Over Studies; Disease Progression; Double-Blind Method; Enzyme Inhibitors; Farnesyltranstransferase; Female; Humans; Male; Neurofibroma, Plexiform; Neurofibromatosis 1; Quinolones; Treatment Outcome; Young Adult
PubMed: 24500418
DOI: 10.1093/neuonc/nou004