Findings showcase the efficacy of agents like EZN-2968, Minnelide, and Acriflavine in modulating HIF-1α protein synthesis and destabilizing HIF-1, providing preliminary proof of HIF-1α mRNA modulation and antitumor activity. However, challenges, including toxicity, necessitate continued exploration and development, as exemplified by ongoing clinical trials. This article concludes by emphasizing the potential of targeted HIF therapies in disrupting cancer-related signaling pathways.

In addition, several triptolide moieties, including minnelide and LLDT8, have progressed in investigations on humans for the treatment of cancer. Targeted strategies, such as triptolide conjugation with ligands or triptolide loaded nano-carriers, are efficient techniques to confront toxicities associated with triptolide. We expect and anticipate that advances in near future, regarding combination therapies of triptolide, might be beneficial against cancerous cells.

P1, N=28, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Jun 2023 --> Dec 2023

Our results demonstrated that, in human CRC xenografts, Minnelide safely and significantly enhances measles virus oncolysis in vivo, leading to improved antitumor effects and prolonged survival. These effects were associated with enhanced antiproliferative and pro-apoptotic effects with the MV-Minnelide combination, suggesting in vivo synergy. Studies characterizing the molecular mechanisms of in vivo synergy and assessing this promising combination in immunocompetent CRC models are underway.

BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier...As a result, the co-delivery of heat shock protein 70 inhibitor VER-155008 with ZnCoFe NCs could realize synergistic magnetic hyperthermia effects upon exposure to an alternating current magnetic field (ACMF) in both GL261 and U87 brain tumor models. This modulation approach brings new ideas for the treatment of central nervous system diseases that require delivery of therapeutic agents across the blood-brain barrier (BBB).

We suggested the combination of IL-15 and PD-1 blocker could enhance the killing potential of AMLNK cells. Moreover, Hsp70 in combination with IL-15 and PD-1 blocker interferes activation of AML-NK cells through unknown mechanisms.

In summary, our study provides a further contribution to the hypothesis of the use of essential oils, from traditional medicinal plants, for the treatment of tumors, and suggests that the combination of our samples with other anti-prostate cancer therapies could be used to affect prostate cancer.

ER level regulated by HSP70 had different significance in laryngeal epithelial cells and LC cells treated with pepsin.

The profound antitumor effects in the aggressive 786-0 RCC xenograft model are highly encouraging and warrant further preclinical studies and potential clinical trials of M this devastating disease. Correlative tumor studies to understand the mechanisms of M in vivo antitumor effects are underway and will be presented at the meeting.

P1b, N=36, Recruiting, Minneamrita Therapeutics LLC | Not yet recruiting --> Recruiting

We conclude that this tumor-lung crosstalk supports primary tumor growth and contributes to anti-PD-1 immunotherapy resistance partially by serving as an anti-PD-1 antibody sink. Pharmacologic inhibition of NLRP3 and HSP70 represents promising strategies for overcoming anti-PD-1 resistance.

P1b, N=36, Not yet recruiting, Minneamrita Therapeutics LLC

Compounds with distinct partitioning have distinct anti-proliferative activity in breast cancer cells compared with anti-viral activity in cellular models of Dengue virus replication, likely because different sets of Hsp70s are required in these processes. These findings highlight the contributions of subcellular partitioning and chemogenetic interactions to small molecule activity, features that are rarely explored during medicinal chemistry campaigns.

Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

Inhibiting HSP70 significantly decreased the cell viability, proliferation, and migration of OSCC cells. HSP70 may be involved in invadopodia-associated proteins in OSCC cells, which provides a promising method for treatment of OSCC metastasis.

Our results characterize myeloma proteostasis networks under therapeutic pressure, motivate further investigation of HSPA9 as a specific vulnerability in PIresistant disease, and suggest “JG” compounds as a promising class of myeloma therapeutics.

Moreover, β-elemene treatment significantly decreased invasion capacity by decreasing the EMT, which was induced by hyperthermia treatment. Taken together, our results offer a potential strategy for CRC therapy via the combination of hyperthermia and β-elemene.

P1b, N=30, Recruiting, City of Hope Medical Center | Initiation date: Jul 2022 --> Mar 2022

Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, whose expression we validated in situ. Last, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro vismodegib-resistant BCC cell growth, Hedgehog signaling, and in vivo tumor growth in a BCC mouse model, validating HSP70's essential role in tumor growth and reinforcing the critical nature of tumor microenvironment cross-talk in BCC progression.

P1b, N=30, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

Minnelide™, an oral anti-super-enhancer drug that inhibits MYC expression in preclinical models of ASCP, has demonstrated safety in a Phase I study. We describe the design for a phase II, open-label, single-arm trial of Minnelide in patients with advanced refractory ASCP.

Moreover, we identified that Bim mediates interactions of Hsp70 and Bak in Bcr-Abl positive cells. Together, the target identification of Hsp70/Bim complex could make it as a promising anticancer target for Bcr-Abl positive leukemia treatment.

Of note, these compounds also effectively suppressed the viability of TT and MZ-CRC-1 progenies resistant to vandetanib and cabozantinib. Moreover, JG-231, an analog with improved microsomal stability, consistently suppressed TT and MZ-CRC-1 xenografts in mice. These data suggest that mortalin inhibition may have therapeutic potential for MTC.

Our results have shown for the first time the potent in vitro and in vivo antitumor effects of T in RCC and the molecular changes associated with these effects. The profound antitumor effects in the aggressive 786-0 RCC xenograft model are highly encouraging and warrant further preclinical studies and potential clinical trials of M this devastating disease. Correlative tumor studies to understand the mechanisms of M in vivo antitumor effects are underway and will be presented at the meeting.

MEK inhibitors are currently used for NRAS-mutant melanoma, but have shown modest efficacy as single agents. This research shows a synergistic effect of combining HSP70 inhibitors with MEK inhibitors for the treatment of NRAS mutant melanoma.

P1b, N=30, Not yet recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Initiation date: Dec 2021 --> Jul 2022 | Trial primary completion date: Dec 2023 --> Dec 2024

Additionally, intracellular and cell surface HSP70s are considered as potential targets for therapy or sensitization of breast cancer. We also discuss a clinical implication of Hsp70s and approaches to targeting breast cancer with gene vectors or nanoparticles downregulating HSP70s, natural or synthetic (small molecule) inhibitors of HSP70s, HSP70-binding antibodies, HSP70-derived peptides, and HSP70-based vaccines.

P1b, N=30, Not yet recruiting, City of Hope Medical Center

Thermal stimulation can promote EMT in A549 and NCI-H446 cells and promote cell migration and invasion in vitro and in vivo by upregulation of Hsp70. This process is associated with the promotion of SUMO modification of HIF-1α.

Omeprazole ameliorates cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90.

Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.

These results suggest that the absence of Hsp70 in the TME inhibits tumors through increased dendritic cell activation. Hsp70 inhibition in DCs may emerge as a novel therapeutic strategy against pancreatic cancer.

Hsp70 may regulate CD24 expression. Co-expression of CD24 and Hsp70 may be a prognostic biomarker for lung cancer.

Pifithrin-μ (PFTμ, HSP70 inhibitor) decreased or removed the effects of peptide in increasing the sensitivity of ovarian cancer cells to DDP. This suggests that PGPIPN enhanced the sensitivity of ovarian cancer cells to DDP partially via reducing the activity of HSF1/HSP70 signaling pathway, thus inducing cell apoptosis and decreasing repairment of DNA damage.

Furthermore, EAS significantly increased progesterone synthesis. Thus, EAS improves HSP70-mediated redox balance and cell function in bovine CG cells.

Skp2 overexpression abrogated HSP70 inhibition-induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy.

Therefore, the results of the present study suggested that HSP70 may inhibit mitochondrial pathway‑mediated apoptosis in isolated neonatal rat PMVECs in early‑stage hypoxia, which may be associated with HSP70‑mediated HIF‑1α downregulation. Overall, HSP70 may be protective against neonatal HPH through the HSP70/HIF‑1α pathway.

Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.

In the present study, we determined the efficacy of Minnelide, a prodrug which is converted to its active form (Triptolide) in vivo against cervical cancer cells. Furthermore, Minnelide treatment was more effective when combined with platinum-based chemotherapy. These studies show that Minnelide can be used to inhibit the growth of cervical cancer.

Our findings reveal that apigenin directs alternative splicing and inhibits Hsp70 enhancing TRAIL anticancer activity. These findings underscore impactful synergies between diet and cancer treatments opening new avenues for improved cancer treatments.

Expectedly, there was no difference in tumor growth and metastasis between control and anti-PDL1 treated animals, however, combination of anti-PDL1 antibody ed with JG-231 and chemotherapy (cyclophosphamide-CTX) significantly reduced primary tumor growth (>10 fold) and eliminated metastasis. Collectively, our pilot experiments provide a strong rationale for testing our hypothesis and may lead to a rapid translation into the clinical utility.