ESK981 / Teva, Esanik Therap - LARVOL DELTA

Dissecting lysosomal metabolic dependencies in pancreatic cancer through functional genomics (AACR 2026) - "To address these issues, here we perform parallel metabolism-focused CRISPR activation and knockout screens using 8 different autophagy or lysosome inhibitors in pancreatic cancer cell lines. From these, we determined that iron homeostasis is primarily affected by agents that affect lysosomal pH, such as bafilomycin A1 and Ammonium, but not by other inhibitors of lysosomal function such as apilimod, ESK981, or chloroquine, or by ULK1 inhibitors ULK101, SBI-0206965, or DCC-3116. Pairing the CRISPR screen data with transcriptomics, we further identified that lipid homeostasis was affected by all lysosome inhibitors but not ULK inhibitors."

Oncology • Pancreatic Cancer • Solid Tumor

Immune implications of dual PIKfyve and KRAS inhibition in pancreatic ductal adenocarcinoma (AACR 2026) - "Thus, building on these findings, we hypothesized that dual inhibition of PIKfyve and KRAS-MAPK signaling modulates the immune landscape of PDAC.Methods & ResultsUsing a syngeneic orthotopic PDAC model, mice underwent 19 days of treatment with PIKfyve inhibitor ESK981 in combination with RAS inhibitor RMC-6236. These suggest that PIKfyve and RAS inhibition alter immune function and prime the microenvironment for immune therapy.Together, our preliminary findings suggest that the combined inhibition of PIKfyve and KRAS-MAPK exerts both direct antitumor effects and enhances the immune response in PDAC. Our goal is to build upon this strategy by leveraging its immune-enhancing effects, particularly with the addition of immune checkpoint blockade."

IO biomarker • Oncology • Pancreatic Ductal Adenocarcinoma • KRAS • PD-L1

BEDB: a comprehensive binding energy database for molecular docking and dynamics: insights into Human Metapneumovirus (HMPV) Inhibitors. (PubMed, Database (Oxford)) - "MK-3207 and Etoposide exhibited docking scores of -10.3 and -9.6, respectively. Additional compounds, including Teniposide, UK432097, 85019940, Setileuton, Orvepitan, Cep-11981, Tadalafil, and VS-5584, were also analyzed, providing further insights into their binding mechanisms and potential therapeutic relevance. The database is developed using PHP, HTML, CSS, JavaScript, and Python and is freely accessible at https://www.pbed.habdsk.org/."

Journal

Dual inhibition of PIKfyve and KRAS/MAPK targets metabolic vulnerabilities of pancreatic ductal adenocarcinoma (AACR 2025) - "Notably, all but one mouse were cured when treated with both ESK981 and MEK inhibitor trametinib. To evaluate the significance of PIKfyve in PDAC, we employed RNA-ISH and found that PIKfyve was significantly higher expressed in PDAC tissue compared to normal surrounding cells. Performing viability screens across multiple PDAC cell lines, we observed that they were highly sensitive to PIKfyve inhibitors apilimod and ESK981. This data suggested that PIKfyve is crucial for PDAC development.We then performed a metabolism-focused CRISPR screen with the selective pressure of PIKfyve inhibition to assess the metabolic role of PIKfyve in PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ACACA • FAS • FASN • KRAS

Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer. (PubMed, Invest New Drugs) - P2 | "(Trial registration: ClinicalTrials.gov NCT04159896. Registration date: November 12, 2019.)."

Combination therapy • Journal • Metastases • P2 data • Castration-Resistant Prostate Cancer • Fatigue • Genito-urinary Cancer • Hematological Disorders • Oncology • Prostate Cancer • Solid Tumor • AR

Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer. (PubMed, Invest New Drugs) - P2 | "(Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018)."

Journal • Metastases • P2 data • Cardiovascular • Genito-urinary Cancer • Hypertension • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

ESK981 and Nivolumab for the Treatment of Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=10 | Terminated | Sponsor: Barbara Ann Karmanos Cancer Institute | N=49 ➔ 10 | Recruiting ➔ Terminated; The study was closed to accrual on 3/1/21 due to safety concerns since 2 patients experienced CVA events.

Combination therapy • Enrollment change • Metastases • Trial termination • Castration-Resistant Prostate Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • TP53

Multicenter Trial of ESK981 in Patients With Select Solid Tumors (clinicaltrials.gov) - P2 | N=66 | Recruiting | Sponsor: University of Michigan Rogel Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Pancreatic Adenocarcinoma • Prostate Cancer • Solid Tumor • CHGA • SYP

Deletion of the lipid kinase PIKfyve in Kras-driven pancreatic genetically engineered mouse model (AACR 2024) - "We demonstrated that the deletion of PIKfyve in pancreatic tissue significantly reduces the pancreatic mass weight compared to the PIKfyve wildtype counterpart and is coupled with less pancreatic intraepithelial neoplasia (PanIN) and PDAC development in KPC and KC mice. Compared to the vehicle treatment, pharmacological inhibition of PIKfyve by ESK981 on KPC mice resulted in a significant increase in the percentage of normal pancreatic tissue and reduced pancreatic lesion development."

Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CK19 • KRAS • KRT19 • TP53

Harnessing PIKfyve as a therapeutic vulnerability in neuroendocrine prostate cancer (AACR 2024) - "In conclusion, our results illuminate the preferential cytotoxicity of PIKfyve inhibition in NEPC tumors compared to AR+ prostate cancer, advocating PIKfyve as a compelling therapeutic target. This study provides a strong rationale for advancing ESK981 into clinical trials for NEPC patients, underscoring its potential in addressing this challenging malignancy."

Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor

Targeting lipid metabolism in pancreatic cancer (AACR 2024) - "Further, we established a patient-derived xenograft model and showed that while the treatment with individual compounds trametinib, MRTX-1133 (KRASG12D inhibitor), and ESK981 all suppressed tumor growth, the combination of ESK981 and trametinib or ESK981 and MRTX-1133 caused substantial tumor regression in nearly all mice. Taken together, targeting lipid metabolism through inhibition of PIKfyve is a promising therapeutic strategy for PDAC, particularly in combination with the numerous KRAS/MAPK inhibitors in clinical development."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ACACA • FAS • FASN • KRAS

Multicenter Trial of ESK981 in Patients With Select Solid Tumors (clinicaltrials.gov) - P2 | N=66 | Not yet recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Jan 2029 ➔ May 2029 | Initiation date: Jan 2024 ➔ May 2024 | Trial primary completion date: Jan 2027 ➔ May 2027

Trial completion date • Trial initiation date • Trial primary completion date • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Pancreatic Adenocarcinoma • Prostate Cancer • Solid Tumor • CHGA • SYP

Multicenter Trial of ESK981 in Patients With Select Solid Tumors (clinicaltrials.gov) - P2 | N=66 | Not yet recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Sep 2028 ➔ Jan 2029 | Initiation date: Oct 2023 ➔ Jan 2024

Trial completion date • Trial initiation date • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Pancreatic Adenocarcinoma • Prostate Cancer • Solid Tumor • CHGA • SYP

Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach. (PubMed, Cell Rep Med) - "This review is a summary of the status of immunotherapy in treating PCa, with a discussion of multiple immune modalities, including vaccines, adoptively transferred T cells, and bispecific T cell engagers, some of which are undergoing clinical trials. In addition, this review also focuses on emerging mechanism-based small-molecule tyrosine kinase inhibitors with immune modulatory properties that, either as single agents or in combination with other immunotherapies, have the potential to improve clinical outcomes."

Clinical data • Journal • Review • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

ERICA: Multi-center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Renal Cell Carcinoma (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Oct 2023 ➔ Oct 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Oct 2023 ➔ Oct 2022; Lack of patient population

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Trial termination • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Multicenter Trial of ESK981 in Patients With Select Solid Tumors (clinicaltrials.gov) - P2 | N=66 | Not yet recruiting | Sponsor: University of Michigan Rogel Cancer Center

New P2 trial • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Pancreatic Adenocarcinoma • Prostate Cancer • Solid Tumor • CHGA • SYP

ESK981 in Treating Patients With Metastatic Castrate-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=13 | Completed | Sponsor: Barbara Ann Karmanos Cancer Institute | Active, not recruiting ➔ Completed | N=27 ➔ 13

Enrollment change • Metastases • Trial completion • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Androgen blockade confers sensitivity to PIKfyve inhibition in prostate cancer (AACR 2023) - "Concurrent treatment with Enzalutamide and ESK981 in vivo triggered greater tumor inhibition and more robust in situ cell death events than either agent alone. Collectively, PIKfyve may have a context-dependent role in AR signaling-dependent and -independent prostate cancer, so that by co-targeting AR signaling and PIKfyve, therapeutic outcome of prostate adenocarcinoma can be improved."

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

Preferential cytotoxicity of ESK981 in neuroendocrine prostate cancer (AACR 2023) - "We demonstrated that ESK981 monotherapy is well tolerated in all in vivo models and ESK981 exerted greater cytotoxicity in NEPC than previous evaluated prostate adenocarcinoma by percent tumor growth inhibition. ESK981 also induced dramatic cell deaths in NEPC preclinical models, determined by H&E staining, TUNEL-positive apoptotic tumor cells, and increased protein level of PARP cleavage via western blotting. Moreover, flow cytometry analysis revealed a dramatic increase in the intratumoral neutrophil infiltration after ESK981 treatment in the NEPC preclinical models in a time-dependent manner."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ITGAM • PTPRC

Novel autophagy inhibitor ESK981 potentiates MEK inhibition cytotoxicity in pancreatic cancer (AACR 2023) - "Finally, using Cell-Titer Glo, we determined that ESK981 and Trametinib had a strong synergistic effect on suppressing cell proliferation (BLISS Score >20) on mouse KPC line 7940B. Taken together, ESK981 is a promising autophagy inhibitor that shows strong anti-proliferative effects on both human and mouse PDAC cell lines as a single agent as well as in combination with Trametinib."

Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Prostate Cancer • Solid Tumor • KRAS • MAP1LC3A

ESK981 in Treating Patients With Metastatic Castrate-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: Barbara Ann Karmanos Cancer Institute | Trial completion date: Oct 2022 ➔ Jun 2023 | Trial primary completion date: Oct 2022 ➔ May 2023

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer. (PubMed, Nat Cancer) - "PIKfyve-knockdown recapitulated ESK981's anti-tumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in advanced prostate cancer patients and be an effective treatment strategy alone or in combination with immunotherapies."

Checkpoint inhibition • IO biomarker • Journal • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Prostate Cancer • Solid Tumor • CXCL10 • IFNG

ERICA: Multi-center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Renal Cell Carcinoma (clinicaltrials.gov) - P2; N=8; Active, not recruiting; Sponsor: University of Michigan Rogel Cancer Center; Recruiting ➔ Active, not recruiting; N=47 ➔ 8

Clinical • Combination therapy • Enrollment change • Enrollment closed • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

ESK981 in Treating Patients With Metastatic Castrate-Resistant Prostate Cancer (clinicaltrials.gov) - P2; N=27; Active, not recruiting; Sponsor: Barbara Ann Karmanos Cancer Institute; Trial completion date: Oct 2020 ➔ Oct 2022; Trial primary completion date: Oct 2020 ➔ Oct 2022

Clinical • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

ERICA: Multi-center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Renal Cell Carcinoma (clinicaltrials.gov) - P2; N=47; Recruiting; Sponsor: University of Michigan Rogel Cancer Center; Suspended ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor