HSF1 could play a notable role in EC progression. HSF1 may be a potential molecular target for both the treatment and prognosis of patients with EC.

Combining HSP70 and HSF1 inhibitors may be a promising anti-cancer strategy, offering a potential solution to overcome the negative feedback mechanism and enhance anti-cancer effects.

Inhibition of Hsp70 upregulation by mEHT was also supported by qPCR and IHC. In conclusion, we suggest that mEHT-therapy combined with HSF1 inhibition can be a possible new strategy of TNBC treatment with great translational potential.

P1, N=7, Terminated, Roswell Park Cancer Institute | N=36 --> 7 | Trial completion date: Aug 2024 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2024 --> Jan 2024; low accrual

Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.

With its important roles in tumorigenesis and tumor progression, targeting HSF1 offers a novel cancer treatment strategy. In this article, we examine the basic function of HSF1 and its regulatory mechanisms, focus on the mechanisms involved in HSF1's roles in different cancer types, and examine current HSF1 inhibitors as novel therapeutics to treat cancers.

HSF1 suppressed expression of CCL5, a chemokine for CD8+ T cells, and upregulation of CCL5 upon HSF1 loss significantly contributed to the recruitment of CD8+ T cells. These findings indicate that HSF1 suppresses antitumor immune activity by reducing CCL5 to limit CD8+ T cell homing to breast tumors and prevent immune-mediated destruction, which has implications for the lack of success of immune modulatory therapies in breast cancer.

Immunohistochemistry confirmed the molecular data. Combined therapy of mEHT and KRIBB11 significantly reduced tumor weight (160.3 mg ± 33.26 mg) further compared to monotherapy (mEHT: 236.8 mg ± 46.42 mg; KRIBB11: 312.3 mg ± 41.45 mg).ConclusionCombined mEHT-therapy with HSF1 inhibition can be a possible new strategy of treating TNBC with a great translational potential.

Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies.

P1, N=61, Recruiting, Nuvectis Pharma, Inc. | N=17 --> 61 | Trial completion date: Apr 2023 --> Jun 2025 | Trial primary completion date: Jan 2023 --> Dec 2024

Using an siRNA approach to determine if activation of the ISR components was contributing to growth inhibition following NXP800 exposure, we found that blocking the induction of ATF4 reduced the response of NXP800-sensitive SK-OV-3 human ovarian carcinoma cells to NXP800 treatment.In summary, NXP800 acts on cancer cells to induce activation of the ISR pathway via GCN2, which then leads to inhibition of HSF1 activation. Further studies are underway to determine the precise molecular target of NXP800 and the mechanism of HSF1 pathway inhibition.