ganetespib (ADX-1612) / Aldeyra - LARVOL DELTA

Harnessing coumarin privilege to achieve potency and selectivity: hypoxia-targeted alkyl coumarin-tethered phenyl quinazolinones as dual hCA IX/HSP90α inhibitors with chemosensitizing activity. (PubMed, RSC Adv) - "Remarkably, 4b also exhibited potent HSP90α inhibitory activity (IC50 = 13.21 nM), comparable to that of ganetespib. Furthermore, 4b preferentially suppressed the proliferation of hypoxic MCF-7 and MDA-MB-231 breast cancer cells, sensitized them to doxorubicin, and induced p53-mediated mitochondrial apoptosis. Molecular docking and molecular dynamics simulations against hCA IX and HSP90α, along with in silico ADME and toxicity studies, further supported the favorable binding behavior, stability, and druglike characteristics of the lead compound."

Journal • Breast Cancer • Oncology • Solid Tumor • CA9 • CDC37 • HSP90AA1

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

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

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 [WITHDRAWN] (AACR 2025) - "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

BPP, a dual functional inhibitor, targets MLL-rearranged acute myeloid leukemia: Unraveling mechanisms and expanding therapeutic horizons (AACR 2024) - "Notably, the combination of ganetespib, an FDA-approved HSP90 inhibitor, with BPP exhibited synergistic effects in both in vitro and in vivo models, inducing synthetic lethality and inhibiting HR repair. Furthermore, BPP not only reduced leukemic stem cells in colony formation assays but also demonstrated sensitivity in relapsed/refractory (R/R) and multiple drug-resistant patient samples. These findings collectively position BPP as a promising candidate for the treatment of MLL-rearranged AML, offering multifaceted therapeutic potential."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CDC37 • FLT3 • GLI2 • KMT2A

HSP90 blockade activates antitumor immunity by suppressing tumor glycolytic flux in head and neck squamous cell carcinoma (AACR 2024) - "Mechanistically, ganetespib downregulates IL8 signaling by inhibiting PKM2 and PFKP-mediated glycolysis in HNSCC cells, which in turn contributes to ganetespib-mediated T cell tumor infiltration. These findings provide a novel molecular basis for the use of effective HSP90 inhibitors to improve the outcome of HNSCC patients."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • CDC37 • CXCL8 • HSP90AA1 • PFKP • PKM

Oncolytic herpes simplex virus expressing XCL1 and FLT3L modulate the intratumoral immune response and improve the anti-tumor efficacy in a metastatic breast tumor model (AACR 2024) - "To enhance the intratumoral penetration of oHSV injected intravenously in primary tumors and MBC lesions in the lung, we employed the cancer drug ganetespib, which can increase the permeability of tumor blood vessels...Further studies are underway to investigate whether the depletion of Treg cells in combination with rQ1-XF enhances effector T cell activation against metastatic breast tumor cells. The findings of this study will provide valuable insights into the effectiveness of using XCL1 and FLT3L-armed oncolytic viruses in patients with MBC."

Metastases • Preclinical • Breast Cancer • Oncology • Solid Tumor • CD4 • CD8 • ITGAM • ITGAX

High IL12family levels are associated with pathologic complete response amongst HER2- patients in the neoadjuvant I-SPY2 TRIAL (AACR 2024) - "Correlations of IL signatures with multiplex immunofluorescence staining of immune infiltrates in the PD1-inhibitor (PD1i) arm were also assessed. High expression of IL signatures in HER2- patients, regardless of HR status, was associated with pCR especially in the Trebananib, Veliparib/Carboplatin (VC) and PD1i arms. In the PD1i arm, expression of almost all IL signatures was highly correlated with density of T, CD8+ cytotoxic T, CD8- T, and B cells and their colocalization with tumor cells; IL-6 signatures correlated with density of proliferating tumor cells.Within RPS subtypes, enrichment of IL signatures in HER2-/Immune+ such as pro-inflammatory IL-1 and IL-12 signaling was associated with pCR in the VC, PD1i, Ganetespib, and control arms... High pre-treatment expression of IL signatures was associated with HER2- receptor and RPS HER2-/Immune+ subtype-specific response to I-SPY2 agents, and the colocalization of immune and tumor cells in the tumor bed. In HER2-..."

Clinical • IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CD8 • HER-2 • IFNG • IL12A • IL6

Dual inhibition of mTOR and HSP90 enhances cisplatin efficacy and overcomes resistance in ovarian cancer. (PubMed, Cell Death Dis) - "Accordingly, the combination of ganetespib (an HSP90 inhibitor) and temsirolimus (a FDA approved-mTOR inhibitor) with cisplatin synergistically reduced colony formation and microtissues cell growth in vitro by increasing DNA-damage and apoptosis and in vivo enhancing mouse survival. Notably, all these data were confirmed also in Pt-resistant Non Small Cell Lung Cancer models. Collectively, our findings identify a promising new antitumor strategy for the treatment of Pt-resistance in cancer patients."

Journal • Epithelial Ovarian Cancer • Gynecology • Oncology • Ovarian Cancer • Solid Tumor • Women's Health • CDC37 • DNAJB1 • HSF1 • HSP90AA1 • RPS6

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

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