US-12616759-B2 - Uses of labeled HSP90 inhibitors

Abstract

This invention concerns various methods of using labeled HSP90 inhibitors to improve treatment of cancer patients with HSP90 inhibitors, including ex vivo and in vivo methods for determining whether a tumor will likely respond to therapy with an HSP90 inhibitor.

Inventors

• Gabriela Chiosis
• Nagavarakishore Pillarsetty
• Jason S. Lewis
• Steven M. Larson
• Tony Taldone
• Mary L. Alpaugh
• Erica M. Gomes-Dagama

Assignees

• SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH

Dates

Publication Date

20260505

Application Date

20230131

Claims (3)

1. 1 . A method for determining whether a tumor in a subject will respond to therapy with an HSP90 inhibitor which comprises the following steps: (a) administering to the subject a radiolabeled HSP90 inhibitor; (b) measuring the amount of radiolabeled HSP90 inhibitor bound to the tumor or the tumor cells in the sample; and (c) comparing the amount of radiolabeled HSP90 inhibitor bound to the tumor or the tumor cells in the sample measured in step (b) to the amount of radiolabeled HSP90 inhibitor bound to a reference; wherein a greater amount of radiolabeled HSP90 inhibitor bound to the tumor or the tumor cells measured in step (b) as compared with the reference amount indicates the tumor will likely respond to the HSP90 inhibitor; wherein the radiolabeled HSP90 inhibitor is a compound or a pharmaceutically acceptable salt thereof of
2. 2 . A compound or a pharmaceutically acceptable salt thereof selected from:
3. 3 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 2 ; and a pharmaceutically acceptable carrier.

Description

1. CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser. No. 16/934,881, filed Jul. 20, 2020, now U.S. Pat. No. 11,607,465, which is a continuation of U.S. application Ser. No. 14/131,420, filed Jun. 12, 2014, which is a U.S. National Stage Application of International Application No. PCT/US2012/045861, filed Jul. 6, 2012, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/506,010, filed Jul. 8, 2011, the contents of all of which are incorporated herein in their entireties by reference thereto. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created Sep. 7, 2023, is named 115872-1076_SequenceListing.xml and is 36,864 bytes in size. 2. BACKGROUND To maintain homeostasis, cells employ intricate molecular machineries comprised of thousands of proteins programmed to execute well-defined functions. Dysregulation of these pathways, through protein mis-expression or mutation, can lead to biological advantages that confer a malignant phenotype. Although at the cellular level such dysregulation may be beneficial (i.e., favoring increased survival), at the molecular level this requires cells to invest energy in maintaining the stability and function of these proteins. It is believed that to maintain these proteins in a pseudo-stable state, cancer cells co-opt molecular chaperones, including HSP9032,33. In support of this hypothesis, HSP90 is recognized to play important roles in maintaining the transformed phenotype32,33. HSP90 and its associated co-chaperones assist in the correct conformational folding of cellular proteins, collectively referred to as “client proteins”, many of which are effectors of signal transduction pathways controlling cell growth, differentiation, the DNA damage response, and cell survival. Tumor cell addiction to deregulated proteins (i.e. through mutations, aberrant expression, improper cellular translocation etc) can thus become critically dependent on HSP9033. The rationale for HSP90 therapy in various forms of cancers is now well-supported by preclinical and clinical studies including in disease resistant to standard therapy91-97. For instance, studies have demonstrated a notable sensitivity of certain HER2+ tumors to HSP90 inhibitors98,99. In these tumors, 17-AAG (also called Tanespimycin) and 17-DMAG (Alvespimycin) elicited responses even, and in particular, in patients with progressive disease after trastuzumab therapy98. Other HSP90 inhibitors, such as PU-H71, when tested pre-clinically in a number of triple-negative breast cancer mouse models, delivered the most potent targeted single-agent anti-tumor effect yet reported in this difficult-to-treat breast cancer subtype100. While these data strongly support the use of HSP90 inhibitors in cancer, there is at the moment no clear consensus on how to identify those patients most-likely to benefit from HSP90 therapy101,102. This is especially problematic knowing that for a successful development of targeted agents it is essential to define the patient subpopulation that should receive the drug (i.e., tumors with EGFR mutations for tarceva). Such selection may reduce the number of patients receiving ineffective treatment and decrease the staggering number of targeted oncology agents that fail in late-stage clinical trials. Further, there is no clinical assay that can non-invasively ascertain HSP90-target inhibition. While pharmacodynamic monitoring of peripheral blood lymphocytes has provided a readily accessible and reproducible index of in vivo biologic activity of HSP90 inhibitors in clinical trials, drug effects in normal tissue do not predict tumor-specific activity97,101,102. Judicious use of biopsies to measure pharmacodynamic changes has remained an important way to assay for target modulation, but this method remains limited because of the logistical and ethical issues associated with invasive assays. As an alternative, changes in the levels of tumor HER2 and VEGF levels is now being investigated using zirconium 89 labeled antibodies103,104 and of soluble HER2 extracellular domain levels in patient sera by ELISA105, but these studies are restricted to the subset of breast tumors that express these biomarkers. Accordingly, there exists a strong need for biomarkers in HSP90 targeted therapy: The majority of cancer patients are treated with novel, experimental therapies, in many cases with little insight into the mechanism of action of the specific agent, the suitability of a particular treatment for different disease subsets, and little knowledge into optimal dose and scheduling of therapeutics in different malignant settings. The end result is empiric clinical investigation, in which patients with refractory malignancies are treated with a spectrum of novel agents without knowledge of which th