onalespib (AT13387)

P1, N=2, Active, not recruiting, National Cancer Institute (NCI)

P1, N=29, Active, not recruiting, National Cancer Institute (NCI)

Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and showed anti-tumor activity in patients with advanced TNBC. Gene expression analysis of patient tumor samples suggest that TNBCs with greater activation of immune checkpoint pathways and those with proteins dependent on HSP90 activity, including p53 and HER2, may be more susceptible to HSP90 inhibition.ClinicalTrials.gov study identification: NCT02474173

Combination therapy showed antitumor activity in patients with advanced TNBC. Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

In this study, we constructed a prognostic model based on PRGs and identified GSDMD as a potential therapeutic target, which provide new insights into SKCM treatment.

P1/2, N=11, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2023 --> Sep 2024

Of them, two market drugs approved by the Food and Drug Administration (AT-13387 and KU-55933) have emerged as candidates for HCC study. This new signature panel may serve as a potential prognostic marker, engendering the possibility of novel personalized therapy with classification of HCC patients.

These findings show promise for Lu-DOTA-M5A as a CRC therapeutic agent, and its combination with onalespib could significantly enhance treatment efficacy. Further in vivo studies are warranted to validate these findings fully and explore the treatment's potential for clinical use.

HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

The efficacy of mobocertinib, amivantamab and poziotinib in NSCLC with EGFR exon 20 insertion mutations is promising. However, therapies were assessed in single-arm CTs with low-quality evidence. Comparative studies with more extensive patient follow-up, larger sample size and better design are needed to reliably quantify the effect of these drugs.

We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.

Finally, mithramycin, MI219, AFP464, aminoflavone, kahalide F, AT13387, doxorubicin, and other drugs increased the sensitivity of cGAS expression. This study discovered that SARS-CoV-2-infected cancer patients might experience changes in their tumor environment as a result of cGAS, making patients with tumors expressing high cGAS more susceptible to COVID-19 and possibly a worsening prognosis. Furthermore, cGAS may be a novel biomarker for diagnosing and treating COVID-19-infected tumor patients.

Our results suggest that [C]SNX-ab is not an ideal probe for in vivo visualization and quantification of Hsp90α/β expression levels in tumour and brain. Future research in the development of next-generation Hsp90 isoform-selective PET tracers is warranted to dissect the role played by each isoform towards disease pathology and support the development of subtype-specific Hsp90 therapeutics.

P1b, N=31, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Drug supply issues

P1/2, N=11, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2022 --> Sep 2023

The results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in GBM patients.

In conclusion, the combination therapy of anti-CEA Lu-DOTA-M5A and onalespib showed enhanced therapeutic effects over the individual monotherapies for the potential treatment of colorectal cancer. Further in vitro and in vivo studies are warranted to confirm the current study findings.

P1b, N=33, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2021 --> Dec 2022

Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs.

Combining onalespib and olaparib was feasible and demonstrated preliminary evidence of anti-tumour activity.

P1/2, N=11, Active, not recruiting, National Cancer Institute (NCI) | N=46 --> 11 | Trial primary completion date: Dec 2021 --> Sep 2021

Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. The selective mutp53 GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53-containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities.

Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338).

AT13387 treatment resulted in pharmacological inhibition of cancer cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence postradiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment.

P2, N=25, Terminated, National Cancer Institute (NCI) | N=50 --> 25 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2021 --> Mar 2021; Drug supply issues

P1/2, N=46, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Jan 2021 --> Dec 2021

P1b, N=33, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2020 --> Dec 2021

P2, N=50, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Oct 2020 --> Oct 2021

This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P. HSP72 was significantly up-regulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and post-treatment tumor biopsy samples. No subjects showed an objective or PSA response Onalespib in combination with AA/P, showed mild evidence of some biological effect, however this effect did not translate into clinical activity, hence further exploration of this combination was not justified.

P1/2, N=46, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Jun 2020 --> Jan 2021

Using the FDA-approved CDK4/6 inhibitors (palbociclib & abemaciclib), we observed that dual inhibition of CDK4 and HSP90 synergistically inhibits cancer viability in colorectal cancer cell lines (eg. HCT116, SW480, DLD1) under both normoxia and hypoxia. Multiple HSP90 inhibitors have been tested, including ganetespib, onalespib, XL888 and TAS116, which indicates such combinational inhibition as a class effect...Hypoxia sensitizes the Rb-deficient MDA-MB-468 breast cancer cell line to abemaciclib treatment. Our findings suggest a therapeutic potential for utilizing the combination of CDK4 and HSP90 inhibitors in cancer treatment.

HSP90 inhibition combined with BRAF/MEK inhibition was determined to be safe with evidence of disease control in a heavily pre-treated population of pts with BRAF V600E/K mut solid tumors. Research Funding: U.S. National Institutes of Health

P1b, N=33, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2019 --> Dec 2020

Consequently, the combination of onalespib and 177Lu‑DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.

P1/2, N=46, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2019 --> Jun 2020