zelavespib intravenous (PU-H71 IV)

P1, N=63, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

These results confirm that HSP90 is a strong pro-survival factor in molecularly heterogeneous gliomas and suggest that epichaperome inhibition with HSP90 inhibitors warrants further investigation for the treatment of gliomas.

Additionally, the present report also suggests the promising role of PU-H71 in JAK2-dependent myeloproliferative neoplasms. Eventually, our report sheds more light on the multiple functions of HSP90 protein as well as the potential therapeutic benefit of its selective inhibitor PU-H71 in the context of an array of diseases, laying the foundations for the development of novel therapeutic approaches that could achieve better treatment outcomes.

The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.

P1, N=63, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90α overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90α overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.

Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity.

Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.

TUS-resistant cells (TUS/R) were 60-fold resistant to gilteritinib (FLT3 inhibitor) but not to quizartinib (FLT3 inhibitor). There was no observed resistance to azacitidine, luxeptinib (lymphoid & myeloid kinase inhibitor), brequinar (DHODH inhibitor), zelavespib (HSP90 inhibitor), or IMP-1088 (NMT1/2 inhibitor), and a small degree of hypersensitivity (<2-fold) of TUS/R cells to luxeptinib, brequinar, and IMP-1088... Resistance to TUS in MOLM-14 cells required prolonged high-level drug exposure. The fact that FLT3 remained fully inhibited in TUS/R cells growing in 75 nM TUS suggests that resistance is not due to a mutation of FLT3. Drug resistance in TUS/R cells in the absence of TUS over 60 days indicates a stable phenotype, distinct from "persister cell resistance" in which resistance fades during subsequent passages.

P1, N=47, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jul 2023 --> Mar 2023 | Trial primary completion date: Jul 2023 --> Mar 2023

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.

The BCL-2 inhibitor venetoclax (VEN)/hypomethylation agent (HMA) combination achieves high response rates, improves outcomes for many patients with AML and is now considered standard of care for patients older or unfit to receive intensive chemotherapy...Importantly, in a 1,000: 1 mixture of TP53-WT and TP53-R248W mutant isogenic Molm13 cells, MDM2 inhibitor nutlin3a selectively killed TP53-WT but enriched TP53-mutant Molm13 cells, as expected, and VEN treatment also favored the outgrowth of TP53-mutant cells...Inhibition of epichaperomes by PU-H71 targets AML cells/stem/progenitor cells, enhances VEN activity, and prevents the outgrowth of nutlin- or VEN-resistant TP53-mutant AML cells. This concept has entered clinical evaluation in MPN-derived secondary AML.