gamitrinib / Fox Chase Cancer Center, The Wistar Institute - LARVOL DELTA

Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies. (PubMed, Mol Cell Biochem) - "Clinical trials are ongoing for the mitochondrial enzyme-targeting agents CPI-613 and Gamitrinib, a heat shock protein-targeting agent, which have hence shown great promise for these therapies. With further investigation, mitochondrial-targeted interventions could be promising for preventing or reducing HCC incidence and recurrence, increasing long-term survival, and improving the quality of life of patients with advanced-stage disease."

Journal • Review • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor

A Phase I Safety and Pharmacokinetic Study of Gamitrinib Administered Intravenously to Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: Fox Chase Cancer Center | Suspended ➔ Recruiting

Enrollment open • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

The differential roles of heat shock protein 90 isoforms in skin inflammation: Anti-inflammatory potential of TRAP1 inhibition. (PubMed, J Invest Dermatol) - "Additionally, a selective-TRAP1 inhibitor (gamitrinib) suppressed the inflammatory gene expression in keratinocytes and fibroblasts (IL17C, IL23A, IL36G) and in hidradenitis suppurativa skin cultured ex vivo (IL1B, IL6, CXCL8, IL17A). In conclusion, selective and simultaneous knockdown of the HSP90 isoforms mediated different inflammatory effects, revealing that the HSP90 isoforms have distinct roles in skin inflammation. In addition, we discovered that inhibition of TRAP1 exerted consistent anti-inflammatory effects, suggesting that TRAP1 inhibitors may represent a topical therapeutic strategy for inflammatory skin diseases."

Journal • Dermatitis • Dermatology • Hidradenitis Suppurativa • Immunology • Inflammation • Psoriasis • CCL20 • CDC37 • CXCL8 • HSP90AA1 • IL17A • IL17C • IL1B • IL23A • IL6

Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target. (PubMed, Genome Med) - "In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs."

Biomarker • IO biomarker • Journal • Brain Cancer • Lung Cancer • Oncology • Solid Tumor • EGFR • LRP1B • MUC16 • TP53 • TTN

A Phase I Safety and Pharmacokinetic Study of Gamitrinib Administered Intravenously to Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=42 | Suspended | Sponsor: Fox Chase Cancer Center | Trial completion date: Dec 2029 ➔ Dec 2026 | Trial primary completion date: Dec 2028 ➔ Jun 2026

Metastases • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Role of the inner mitochondrial membrane protein (Mic60) in MAPKi-resistant melanoma (AACR 2024) - "Mic60 is heterogeneously expressed and often reduced in melanoma. Although this is associated with increased cell invasion and metastatic propensity, the combination of Gamitrinib plus MAPKi restored mitochondrial cell death in therapy-resistant, Mic60-low melanoma cells."

Genito-urinary Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor • CDC37

The development of cancers research based on mitochondrial heat shock protein 90. (PubMed, Front Oncol) - "Among these compounds, gamitrinib, a specific mtHsp90 inhibitor, has demonstrated its safety and efficacy in several preclinical investigations and is currently undergoing evaluation in clinical trials. This review aims to provide a comprehensive overview of the present knowledge pertaining to mtHsp90, encompassing its structure and function. Moreover, our main emphasis is on the development of mtHsp90 inhibitors for various cancer therapies, to present a thorough overview of the recent pre-clinical and clinical advancements in this field."

Journal • Review • Oncology • TNFA

Inhibition of TRAP1 Accelerates the DNA Damage Response, Activation of the Heat Shock Response and Metabolic Reprogramming in Colon Cancer Cells. (PubMed, Front Biosci (Landmark Ed)) - "These findings provide new insights into TRAP1-driven metabolic reprogramming in response to oxidative stress."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HSF1 • HSP90AA1 • TNFA

Synergistically suppressive effects by combination of glycolytic inhibitor with TRAP1-depletion in colorectal cancer (AACR 2023) - "To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer...Taken together, depletion of TRAP1 induces mitochondrial dysfunction and modulates metabolic switch toward aerobic glycolysis in TRAP1-depleted colon cancer cells. Dual inhibition of TRAP1 and glycolytic signaling may increase therapeutic efficiency through induction of excessive ROS production in colon cancer."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HSP90AA1 • TNFA

A Phase I Safety and Pharmacokinetic Study of Gamitrinib Administered Intravenously to Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=42 | Suspended | Sponsor: Fox Chase Cancer Center | Recruiting ➔ Suspended

Metastases • Trial suspension • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Loss of function of CDK7 is synthetically lethal with fatty acid oxidation inhibition in glioblastoma (SNO 2022) - "Consistently, the combination treatment of CDK7i inhibitors with blockers of FAO (etomoxir) or cellular respiration (gamitrinib) exerted substantial synergistic growth inhibition in patient derived xenograft as well as neurosphere GBM cultures, which was mainly driven by a collapse of oxidative energy metabolism. Finally, the combined administration of YKL-5-124 and etomoxir extended overall in an orthotopic patient-derived xenograft model of GBM. In summary, these data support that simultaneous targeting of CDK7 and FAO might be a potential novel therapy against GBM."

Synthetic lethality • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2L1 • CDK7 • MCL1

Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance. (PubMed, Cells) - "Several HSP90 inhibitors-such as geldanamycin and its derivatives, gamitrinib and shepherdin-are under clinical evaluation with promising results. Here, we review the subcellular localization of HSP90, its corresponding mechanism of action in the malignant phenotypes, and the recent progress on the development of HSP90 inhibitors. Hopefully, this comprehensive review will shed light on the translational potential of HSP90 inhibitors as novel cancer therapeutics."

Journal • Review • Oncology • HSP90AA1

Metabolic targeting of NRF2 potentiates the efficacy of the TRAP1 inhibitor G-TPP through reduction of ROS detoxification in colorectal cancer. (PubMed, Cancer Lett) - "To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer...Furthermore, treatment with both a NRF2 inhibitor and a TRAP1 inhibitor led to excessive ROS production and exacerbated G-TPP-induced cell death in G-TPP-resistant cells. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome colon cancer resistance by raising cellular ROS levels above the cytotoxic threshold."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HSP90AA1 • HSPA5 • NQO1 • TNFA

Metabolic targeting of NRF2 potentiates the efficacy of TRAP1 inhibitor GTPP in colorectal cancer (AACR 2022) - "Inhibition of TRAP1 by a small molecule inhibitor, Gamitrinib-triphenylphosphonium (GTPP), in colon cancer cells led to ROS production, ER stress, reduction of cell viability and induction of cell death...These new findings for the first-time link TRAP1 and NRF2 in a common pathway regulating ROS production in colon cancer. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome the tumor cell resistance through disruption of mitochondrial redox homeostasis."

Clinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HSP90AA1 • HSPA5 • NQO1 • TNFA

Anti-tumor Activity of a Mitochondrial Targeted HSP90 Inhibitor in Gliomas. (PubMed, Clin Cancer Res) - "These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary anti-tumor mechanisms in gliomas."

Journal • Brain Cancer • Glioma • Immunology • Oncology • Solid Tumor

Feasibility and safety of targeting mitochondria for cancer therapy - preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor. (PubMed, Cancer Biol Ther) - P1 | "Therefore, targeting mitochondria for cancer therapy is feasible and well tolerated. A publicly funded, first-in-human phase I clinical trial of Gamitrinib in patients with advanced cancer is ongoing (ClinicalTrials.gov NCT04827810)."

Journal • Preclinical • Immunology • Inflammation • Oncology • CYP1A2 • CYP2C8 • HSP90AA1 • KCNQ1OT1

A Phase I Safety and Pharmacokinetic Study of Gamitrinib Administered Intravenously to Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=42; Recruiting; Sponsor: Fox Chase Cancer Center; Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Fox Chase Cancer Center, The Wistar Institute Announce Opening of Phase 1 Clinical Trial of Anticancer Drug Candidate (FoxChaseCancerCenter) - "'We are excited to share the news that the gamitrinib trial is now open for accrual. We hope to make progress in this very first step toward a promising new treatment for patients with advanced cancer, where there remains a high unmet need for new, effective therapies,' said Olszanski."

Media quote