ganetespib (ADX-1612) / Aldeyra - LARVOL DELTA

IL-1-driven signaling promotes resistance to PI3K and BCL2 inhibitors in B-cell lymphoma preclinical models (AACR 2026) - "A 1,400-compound FDA-approved library was used in combination with copanlisib/venetoclax. VL51 cells with acquired resistance to PI3K/BCL2 inhibitors were characterized by an upregulation of IL1α and IL1β, elevated ERK and STAT3 phosphorylation, and increased expression of pro-survival and cytokine-responsive proteins. IL-1-driven reprogramming promotes resistance to PI3K and BCL2 inhibition in B-cell lymphoma via activation of NF-κB, STAT3, and metabolic survival pathways. Targeting IL-1 signaling or downstream effectors may overcome resistance and offer a promising therapeutic strategy for relapsed or refractory B-cell lymphomas."

IO biomarker • Preclinical • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ALDH1A1 • AURKA • IL1A • IL1B

Heat shock protein inhibitors suppress cytokine-induced DUOX2 mRNA and protein expression in human pancreatic cancer cells in a JAK, STAT dependent manner (AACR 2026) - "Using a panel of human pancreatic cancer cell lines (BxPC-3, AsPC-1 and CFPAC-1), we found that two different Hsp90 inhibitors, Tanespimycin (17-AAG) and Ganetespib (STA-9090), inhibit JAK1 and JAK2 kinases, blocking cytokine-induced, JAK-regulated STAT phosphorylation...Furthermore, the JAK1/2 inhibitor Ruxolitinib inhibits IL-4 induced and JAK-mediated STAT6 phosphorylation, and DUOX2 mRNA and protein expression in BxPC-3 cells...Either remaining Hsp90 protein or other isoforms of Hsp90 in cells may compensate decreased Hsp90 function after siRNA knockdown. Our data suggests that Hsp90 inhibitors, through blocking the cytokine-activated JAK-STATs oncogenic signaling pathway and their downstream genes such as DUOX2, VEGF-A, MMP-7 and PD-L1expression, may be a valuable therapeutic approach for inflammation-associated pancreatic cancer."

IO biomarker • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CDC37 • DUOX2 • HIF1A • IFNA1 • IL17A • IL4 • MMP7 • PD-L1 • STAT1 • STAT3 • STAT6

Fulvestrant With or Without Ganetespib in HR+ Breast Cancer (clinicaltrials.gov) - P2 | N=50 | Completed | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PGR

ENGOT-ov48/EUDARIO: European trial on enhanced DNA repair inhibition in ovarian cancer (ESMO 2024) - P2 | "This supports using HSP90i in combination with Carboplatin (C) to induce mitotic catastrophe and with PARPi to create a BRCA-like phenotype in ovarian cancer (OC). This is a multicentre, open-label, three-arm randomized Phase II trial assessing the HSP90i Ganetespib (G) in combination with C followed by maintenance treatment with Niraparib (N) (experimental arm B) versus G/C followed by G&N (experimental arm C) versus standard platinum-based chemotherapy combinations followed by N (standard arm A) in patients with platinum-sensitive (pls) OC. EUDARIO is the first trial to combine an HSP90i with C and PARPi in OC and has not shown improved outcome. Based on its unique biobank, it provides valuable translational findings, such as encouraging the analysis of liquid biopsies for therapy monitoring and prognostication in patients with pls OC."

Late-breaking abstract • Gynecologic Cancers • Oncology • Ovarian Cancer • Sarcoma • BRCA • BRCA1 • CDC37 • CDH5 • CHEK1 • FXYD3 • HER-2

Alkaline Phosphatase-Activated NIR-II AIEgens Nanosystem for Surgical and Postoperative Closed-Loop Therapy of Advanced Osteosarcoma. (PubMed, Adv Sci (Weinh)) - "NIR irradiation induces pyroptosis via caspase-3/GSDME activation and immunogenic cell death, while Ganetespib suppresses glycolysis (HK2/PKM2 downregulation) to reverse lactate-driven immunosuppression. This dual-action strategy synergistically enhances T-cell infiltration and ablates residual/metastatic lesions, offering a transformative approach for unresectable Osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3 • CDC37 • GSDME • PKM

Neoadjuvant HSP90 inhibition with ganetespib significantly improves distant relapse-free survival in I-SPY2 patients with HER2-negative breast cancer with low expression of immune genes and no DNA repair deficiency (SABCS 2025) - P2 | "Here, we re-evaluate the ganetespib arm by Response Predictive Subtypes with 5-year median follow-up data, focused on patients with breast tumors of the HER2-/Immune-/DRD- subtype. HER2-/Immune-/DRD- patients (N=221; 79% HR+, 21% TN) and HER2-/Immune+ and/or DRD+ patients (N=219; 32% HR+, 68% TN) were randomized to neoadjuvant ganetespib (150 mg/m2 ganetespib every 3 weeks with paclitaxel, then doxorubicin plus cyclophosphamide (AC)) (n=38 HER2-/Immune-/DRD- and n=55 HER2-/Immune+ and/or DRD+), or standard neoadjuvant chemotherapy control (paclitaxel-AC) (n=183 HER2-/Immune-/DRD- and n=164 HER2-/Immune+ and/or DRD+). Our data suggest a promising role for ganetespib in improving long-term outcomes for patients with HER2-/Immune-/DRD- tumors, which account for 38% of all molecularly high-risk breast cancers, even in the absence of a pathologic complete response. Continuous measures of RCB and FTV may serve as early predictors of ganetespib's long-term survival..."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37 • DRD • HER-2 • HSP90AA1

Radiosensitization of NET cells by HSP90 inhibitor ganetespib is mediated through pleiotropic stress responses. (PubMed, EJNMMI Res) - "Given the lack of significant effects on direct DNA repair or transcriptomic responses, our findings suggest that HSP90 inhibition radiosensitizes NET cells by inducing a pleiotropic effect on multiple stress-related pathways at the protein level, rather than solely through disruption of DNA damage response mechanisms. This effect is likely driven by loss of HSP90 function and subsequent cumulated unfolded protein and proteotoxic stress."

Journal • Neuroendocrine Tumor • Oncology • Solid Tumor • CDC37 • RAD51 • SSTR • SSTR2 • TP53BP1

Chrono-Pharmacology for Cancer: Harnessing Circadian Regulations of the Cell Cycle and Immune Response Dynamics for Precision Therapy. (PubMed, ACS Pharmacol Transl Sci) - "We discussed some interesting examples, like HSP90 inhibitors (ganetespib), HDAC inhibitors (quisinostat), topoisomerase inhibitors (doxorubicin), and BCL-2 family antagonists (Obatoclax, TW-37), whose therapeutic activities are tightly regulated by circadian control over their molecular targets, pharmacokinetic processes, and downstream physiological pathways. Furthermore, the circadian influence extends to the tumor microenvironment and antitumor immunity, suggesting novel chrono-immunotherapy approaches. By putting together the molecular bases of these temporal dynamics, this review underscores the significant potential of chronotherapythe timed administration of drugs to improve cancer treatment by enhancing therapeutic indices and paving the way for personalized, temporally optimized oncology strategies."

Journal • Review • Oncology • Targeted Protein Degradation • ARNTL • BCL2 • BMAL1 • CDC37 • CDKN1A • FBXW7

Ex Vivod Qualitative and Quantitative Analysis of Fluorescently-Labeled Hsp90 Drug in Human TumorsRunning Title: Ex vivo evaluation of Hsp90 drugs. (PubMed, Cell Stress Chaperones) - "This protocol combines flow cytometry and confocal microscopy to quantitatively and visually assess ganetespib uptake, providing insight into drug distribution and therapeutic response in human cancers. For complete details on the use and execution of this protocol, please refer to 1,2."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CDC37 • HSP90AA1

Synergistic Inhibition of PI3K and HSP90 Enhanced Antitumorigenic Efficacy in Adrenocortical Carcinoma. (PubMed, Res Sq) - "Quantitative high-throughput drug combination screening identified potent synergy between phosphatidylinositol-3-kinase (PI3K) inhibitor, PIK75 and heat shock protein 90 (HSP90) inhibitors, Ganetespib (STA9090), HSP990, or Luminespib (NVP-AUY922). Further antitumor efficacy was confirmed by the BGT226-STA9090 combination in human ACC xenograft model and five PDOs with different pathogenic mutations. Conclusively, the combinations of PI3K and HSP90 inhibitors were highly effective in preclinical studies, warranting a clinical trial in patients with advanced ACC."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CDC37 • HSP90AA1

Ganetespib as an inhibitor of heat shock protein 90 alleviates pulmonary fibrosis by inhibiting the Wnt/β-catenin signaling pathway. (PubMed, Int Immunopharmacol) - "Overall, these results suggest that inhibition of HSP90 expression alleviates pulmonary fibrosis in vitro and in vivo. Therefore, HSP90 may be a potential strategy for the treatment of pulmonary fibrosis."

Journal • Immunology • Inflammation • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • CDC37 • MYC

STK32C as a Therapeutic Target in Colorectal Cancer via HSP90-PI3K/AKT/mTOR Signaling. (PubMed, Int J Biol Sci) - "Emerging evidence implicates serine/threonine kinase 32C (STK32C) overexpressed in bladder cancer and brain tissues acts as a molecular target for doxorubicin resistance, yet its role in colorectal cancer (CRC) remains unclear...Consistently, STK32C depletion or HSP90 N-terminal inhibitor Ganetespib reduced STK32C and p-AKT1, while the HSP90 C-terminal inhibitor, epigallocatechin gallate (EGCG) or AKT inhibitor LY294002 did not affect STK32C, implying that STK32C acts as an upstream of AKT. Furthermore, STK32C depletion enhanced 5-fluorouracil (5-FU) efficacy, with synergistic effects confirmed by CompuSyn and SynergyFinder analysis. In vivo, STK32C depletion reduced the growth of HCT116 cells in BALB/c mice with decreased expression of STK32C, HSP90, PCNA, and AKT and activated caspase 3. Overall, these findings suggest STK32C as a novel oncogenic driver in CRC that modulates HSP90 and PI3K/AKT/mTOR signaling and highlights its potential as a therapeutic target alone or..."

IO biomarker • Journal • Brain Cancer • Colorectal Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • ANXA5 • BCL2 • CASP3 • CDC37 • HSP90AA1 • PARP1 • PCNA

Clonal Hematopoiesis in Whole-Blood and Cell-Free DNA of Ovarian Cancer Patients Undergoing PARP-Inhibitor Treatment: An Exploratory Analysis of the ENGOT-ov48/Eudario Trial (ASH 2023) - P2 | "Study treatment consisted of six cycles of carboplatin-based chemotherapy followed by maintenance therapy with Niraparib ± the HSP90 inhibitor Ganetespib. In summary, our data reveals a high prevalence of CH in patients with relapsed HGOC and provides novel insights into the clonal architecture and dynamics of CH under carboplatin and PARPi treatment with a differential selection of DDR-driven clones. Moreover, we report a relevant interference of CH-derived mutations with tumor-derived mutations in cfDNA."

Cell-free DNA • Clinical • Hematological Malignancies • Infectious Disease • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • CDC37 • DNMT3A • PPM1D • TET2 • TP53

Clonal Hematopoiesis in Whole-Blood and Cell-Free DNA of Ovarian Cancer Patients Undergoing PARP-Inhibitor Treatment: An Exploratory Analysis of the ENGOT-ov48/Eudario Trial (ASH 2023) - P2 | "Study treatment consisted of six cycles of carboplatin-based chemotherapy followed by maintenance therapy with Niraparib ± the HSP90 inhibitor Ganetespib. In summary, our data reveals a high prevalence of CH in patients with relapsed HGOC and provides novel insights into the clonal architecture and dynamics of CH under carboplatin and PARPi treatment with a differential selection of DDR-driven clones. Moreover, we report a relevant interference of CH-derived mutations with tumor-derived mutations in cfDNA."

Cell-free DNA • Clinical • Hematological Malignancies • Infectious Disease • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • CDC37 • DNMT3A • PPM1D • TET2 • TP53

Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy. (PubMed, Cell Death Differ) - "Furthermore, our results demonstrated that the combination of Elesclomol with HSP90 inhibitor Ganetespib exhibited synergistic anti-tumor effects. In conclusion, our findings that mitochondria-translocated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy can provide critical insights into developing effective pro-oxidative therapies against tumors."

Journal • Oncology • CDC37 • LONP1 • TFAM

HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells. (PubMed, Int J Mol Sci) - "Collectively, these findings demonstrate that HSP90 inhibition by ganetespib mitigates 27OHChol-driven monocytic cell activation through suppression of the HSP90-Akt/mTORC1 axis. Targeting this pathway may provide a promising therapeutic strategy for metabolic inflammation associated with oxysterols."

Journal • Inflammation • CCL2 • CD80 • CD83 • CDC37 • EIF4EBP1 • HSP90AA1 • MMP9

Functional personalized complex combination nano therapy for osteosarcoma. (PubMed, Sci Rep) - "We identified promising non-chemotherapeutic drug pairs, including trametinib-ponatinib and rapamycin-ganetespib and demonstrated potent synergistic effects. Surprisingly, alternating administration of nanoparticle drug pairs was superior to concomitant regimen in both efficacy, survival and toxicity profiles. These findings strengthen a functional approach for combinatorial personalized treatment, potentially overcoming the limitations of current therapeutic strategies."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • KRAS

Functional personalized complex combination nano therapy for osteosarcoma (Nature) - "We started with a systematic screening of 17 drugs from multiple classes across four osteosarcoma cell lines (U2OS, MG-63, SaOS-2, and K7M2), and observed differential drug responses among the cell lines. Interestingly, leading large language models (LLMs) failed to predict cell specific efficacy in OS cells while they were successful in KRAS mutation driven cells. Both SaOS-2 and K7M2 showed sensitivity to kinase inhibitors, particularly ponatinib, and we further explored their combinatorial therapeutic potential. We identified promising non-chemotherapeutic drug pairs, including trametinib-ponatinib and rapamycin-ganetespib and demonstrated potent synergistic effects."

Preclinical • Osteosarcoma

Patient-Derived Tumoroid Xenograft Models for Preclinical Validation of Therapeutics in Pleural Mesothelioma (IMIG 2025) - "We tested the efficacy of romidepsin (a histone deacetylase inhibitor), sepantronium bromide (SB; a survivin inhibitor), and cisplatin-pemetrexed (CP; standard of care). These tumoroid-based xenograft models effectively recapitulate PM heterogeneity and provide a robust platform for therapeutic testing. Preliminary findings suggest survivin inhibition with sepantronium bromide as a promising strategy, meriting further experiments on different tumoroid cultures. In addition, further drug candidates showing promising yet more tumor-specific susceptibility profiles are currently under investigation, including ixazomib, a proteasome inhibitor, and ganetespib, a heat shock protein 90 (HSP90) inhibitor."

Preclinical • Giant Cell Tumor of Bone • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • BIRC5 • CDC37 • HSP90AA1 • VIM

Preclinical evaluation of [ 11 C]Onalespib for Heat Shock Protein 90 (HSP90) cancer imaging (EANM 2025) - "Binding specificity was assessed by pre-incubation with vehicle or Hsp90 inhibitors (Onalespib, HSP990, TAS-116, PU-H71, Ganetespib) prior to tracer exposure. While tumour uptake is modest, [¹¹C]Onalespib offers a promising scaffold for Hsp90-targeted imaging and potential theranostic applications. Further studies optimizing tumour delivery and exploring radiolabelling with longer-lived isotopes could enhance its translational potential."

Preclinical • Brain Cancer • Gastrointestinal Disorder • Glioblastoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CDC37 • HSP90AA1

Integrating deep learning for post-translational modifications crosstalk on Hsp90 and drug binding. (PubMed, J Biol Chem) - "We demonstrated that deletion of histone deacetylase 3 (HDAC3) and histone deacetylase 8 (HDAC8) in human cells led to increased binding of Hsp90 to both ATP and its ATP-competitive inhibitor, Ganetespib...We used both a deep-learning artificial intelligence (AI) prediction model and data based on mass-spectrometry analysis of Hsp90 isolated from the mammalian cells bound to its drugs to decipher PTM crosstalk. The alignment of data from both methods demonstrates that the deep-learning prediction model offers a highly efficient and rapid approach for deciphering PTM crosstalk on complex proteins such as Hsp90."

Journal • Oncology • CDC37 • HDAC3 • HDAC8 • HSP90AA1

Cancer Cell-Mimicking Prussian Blue Nanoplatform for Synergistic Mild Photothermal/Chemotherapy via Heat Shock Protein Inhibition. (PubMed, ACS Appl Mater Interfaces) - "In detail, the colon cancer cell membrane (CT26M)-camouflaged HSP90 inhibitor ganetespib and the chemotherapeutic agent doxorubicin (DOX)-coloaded hollow mesoporous Prussian blue (HMPB) nanoplatform (named PGDM) were designed for synergistic mild photothermal/chemotherapy via HSP inhibition. The results confirmed that the combined treatment regimen of mild photothermal therapy (PTT) and chemotherapy showed a better therapeutic efficacy than the individual treatment methods. Therefore, this multimodal nanoparticle can advance the development of drugs for the treatment of malignancies, such as colon cancer, and has prospects for clinical application."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDC37

Recent advances in HSP90 inhibitors as targeted cancer therapy: Chemical scaffolds, isoform selectivity, and clinical progress. (PubMed, Bioorg Chem) - "Despite extensive research, pimitespib remains the only approved HSP90 inhibitor, while others like ganetespib (STA-9090) and onalespib (AT13387) are undergoing clinical trials with variable outcomes (varying efficacy and tolerability profiles). Over the past five years, significant progress has been made in the medicinal chemistry and chemical biology of HSP90 inhibitors. This review comprehensively summarizes advancements from 2020 to 2024 in the discovery and development of HSP90 inhibitors, spanning natural products and synthetic small molecules, with detailed discussions on their preclinical and clinical development, alongside the challenges faced in translating these inhibitors into effective anticancer agents."

Journal • Review • Oncology • CDC37 • HER-2 • TP53

Preclinical Investigation Of Phosphatidylinositol-3-kinase And Heat Shock Protein 90 Inhibitors Combination Therapy In Adrenocortical Carcinoma (ENDO 2025) - "We determined the effective doses and cytotoxicity of the HSP90 inhibitors (STA9090, HSP990, NVP-AUY922) and PI3K inhibitors (PIK-75, BGT-226) and their combinations in preclinical models of ACC. Further validation of synergistic efficacy of BGT226 and STA9090 in NOD SCID-gamma mice showed a reduction in the mean volume of ACC xenografts in STA9090-BGT226 treatment group to 28.4% of the vehicle control group and 38.4% and 37.7 % of those in STA9090-only and BGT226-only groups, respectively. In conclusion, the synergistic combinations of the PI3K and HSP90 inhibitors were effective in preclinical studies of ACC, warranting a clinical trial in patients with advanced ACC."

Combination therapy • Late-breaking abstract • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT2 • CDC37 • HSP90AB1 • PIK3R1

Preclinical Investigation Of Phosphatidylinositol-3-kinase And Heat Shock Protein 90 Inhibitors Combination Therapy In Adrenocortical Carcinoma (ENDO 2025) - "We determined the effective doses and cytotoxicity of the HSP90 inhibitors (STA9090, HSP990, NVP-AUY922) and PI3K inhibitors (PIK-75, BGT-226) and their combinations in preclinical models of ACC. Further validation of synergistic efficacy of BGT226 and STA9090 in NOD SCID-gamma mice showed a reduction in the mean volume of ACC xenografts in STA9090-BGT226 treatment group to 28.4% of the vehicle control group and 38.4% and 37.7 % of those in STA9090-only and BGT226-only groups, respectively. In conclusion, the synergistic combinations of the PI3K and HSP90 inhibitors were effective in preclinical studies of ACC, warranting a clinical trial in patients with advanced ACC."

Combination therapy • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT2 • CDC37 • HSP90AB1 • PIK3R1