Measuring Tumor Epichaperome Expression Using [¹²⁴I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer

Abstract

PURPOSE Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU–positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker. METHODS We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit. RESULTS Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m2 plus nab-paclitaxel 260 mg/m2 administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels. CONCLUSION The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.

The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders

“…This would be evident because HSP90 is one of the most abundantly expressed proteins in a cell (see Section 2.3 above). This is decidedly not the case, indicating that uptake is highly specific for epichaperomes (Bolaender et al, 2021;Inda et al, 2020;Jhaveri et al, 2020;Merugu et al, 2020;Pillarsetty et al, 2019;Sugita et al, 2021).…”

“…Whereas each of these chaperones is an abundant protein, and found in all cells in the human body, the fraction of a chaperone incorporated into epichaperomes is minor and localized to diseased cells and tissues (Inda et al, 2020;Kishinevsky et al, 2018;Rodina et al, 2016;Yan et al, 2020). Importantly, this critical finding makes the epichaperome optimal for both targeting and imaging (Bolaender et al, 2021;Dunphy et al, 2020;Inda et al, 2020;Jhaveri et al, 2020;Pillarsetty et al, 2019;Sugita et al, 2021).…”

“…The spatio-temporal analysis of epichaperome expression in the PS19 mouse model of tauopathy showed its specific presence in disease-relevant regions of the brain but no expression in age-matched mice even at advanced age and despite similar overall expression of chaperones in both the Tg and the WT mice (Inda et al, 2020). Whole-body epichaperome imaging data by positron emission tomography (PET) is now emerging from both mice and humans to indicate disease specific presentation irrespective of age (Bolaender et al, 2021;Jhaveri et al, 2020;Pillarsetty et al, 2019). This body of evidence indicates that, if epichaperomes form in the organism undergoing normal aging, they are either transient in nature and/or form at an expression level that is undetectable by sensitive techniques such as PET.…”

“…To put PU-H71 in this context, its dissociation from HSP90 occurs in minutes whereas its off-rate from epichaperomes is in contrast measured in days (Jhaveri et al, 2020;Pillarsetty et al, 2019;Rodina et al, 2016). Since PU-H71 kinetically discriminates the small fraction of HSP90 in epichaperome from the abundant HSP90 pools found along epichaperomes in the same cell and throughout the body, radiolabeled or fluorescently-labeled versions of PU-H71 can be used as in vivo epichaperome detection reagents (Figure 3a) (Bolaender et al, 2021;Inda et al, 2020;Jhaveri et al, 2020;Merugu et al, 2020;Pillarsetty et al, 2019;Sugita et al, 2021). If the in vivo off-target of PU-H71 (and PU-AD, see further) was the chaperone HSP90, high nonspecific uptake would occur not only in all epichaperome-positive tumors but also in epichaperome-negative tumors and in all tissues and organs.…”

Oncogenic HSP90 Facilitates Metabolic Alterations in Aggressive B-cell Lymphomas

“…S6B). We further evaluated this effect by measuring inosine, lactate and arginine in the plasma of four DLBCL patients with tumors with high 124 I-PU-H71 uptake that non-invasively indicates the presence of active oncogenic HSP90 in cancer tissues (25,42,43). DLBCL patients were intravenously administered a single dose of PU-H71 (equivalent to 75 mg/kg in mice), and plasma was obtained before and 4 and 24 h after (27).…”