Background: TNBC an unmet medical need: Triple negative breast cancer (TNBC), a subtype of breast cancer that lacks expression of an estrogen receptor (ER), a progesterone receptor (PR), and HER2, presents a particularly difficult therapeutic challenge as this phenotype is characterized by its aggressive nature and relative lack of targeted strategies. It is characterized by its unique molecular profile and distinct pattern of metastasis. Epidemiological studies show a high prevalence of triple negative breast cancer among younger women and those of African descent. Although initially sensitive to chemotherapy, early relapse is common, and a predilection for visceral metastasis has been described. The absence of tumor-specific treatment options in this cancer subset underscores the critical need to develop a better understanding of the biology of this disease, as well as to advance treatment strategies for these patients. Background: Hsp90 as a potent target in TNBC: We have recently shown that Hsp90 is an especially promising target in this aggressive and heterogeneous breast cancer subtype, and have proposed the used of Hsp90 inhibitors in the treatment of these women (Caldas et al, PNAS 2009). With several Hsp90 inhibitors currently in clinical investigation, evaluation of Hsp90 inhibitors in TNBC is thus, a timely proposition. Hypothesis: Targeted therapies are best used in the appropriate molecular context. Despite this, the majority of randomized phase III trials-the defining hurdle for regulatory approval-continue to be designed for unselected patient populations. With the exception of a few targeted agents in molecularly well-defined diseases (eg, imatinib in gastrointestinal stromal tumors with activating KIT mutations), outcomes of clinical trials of targeted therapies have been at best modest, probably reflecting the hitherto lack of individualized, treatment approaches based on molecular alterations. Thus, for a rational and a biomarker-driven clinical strategy for Hsp90 inhibitors, we hypothesize that the development and implementation of predictive biomarkers for patient selection and trial enrichment prospects is necessary. Approach: Individual cancers are likely to have distinct biologic drivers, which can be exploited therapeutically by an appropriate targeted agent. Using a novel chemical biology/proteomics approach, we identified that in TNBC, Hsp90 regulates p-Akt and Bcl-xL, and have shown that their expression is potentially predictive of high apoptotic response to Hsp90 inhibition. We hypothesize here that these anti-apoptotic drivers are useful biomarkers in the selection of TNBC patients more likely to benefit from Hsp90 therapy. To demonstrate this hypothesis, our application aims to establish a correlative relationship between the ex vivo sensitivity of TNBC tumors to Hsp90 inhibitors and the expression of these select biomarkers. To do so, it will use fresh patient samples to:
Aim 1. test ex vivo the sensitivity of patient TNBC tumor specimens to Hsp90 inhibitor (Hsp90i).
Aim 2. examine the expression of biomarkers by immunohistochemistry (IHC) and Western blot (WB), score and develop a correlative relationship between biomarker expression and Hsp90i sensitivity This exploratory correlation analysis of tumor sensitivity vs biomarker profile will provide a scoring system for predictive response of TNBC tumors to Hsp90i. This system will be validated in a Phase I clinical trial and in a larger Phase II cohort (not covered in the R21). The ultimate goal is to provide a means by which patient selection for future Hsp90i treatment in TNBC would be routinely performed on formalin-fixed paraffin- embedded (FFPE) specimens or in circulating tumor cells. Significance: The proposed scoring system has the potential for increasing the odds for a successful and efficient transition of Hsp90 inhibitors through the drug development pipeline in TNBC. We propose that the incorporation of scientifically and analytically validated biomarkers, as described here, into rationally designed hypothesis-testing clinical trials offers a promising forward direction towards a successful targeted therapy in TNBC, and promises that personalized medicine can be a reality in this setting.
Despite of the large number of potential new agents entering clinical evaluation every year, only 5% to 8% ever reach registration. Of particular concern is the high rate of failures in Phase 3, where an estimated 50% of oncology agents are stopped in development. Such failures are especially expensive and deprive many patients of potentially more effective treatments. These dire statistics clearly speak for the need to discover and implement predictive biomarkers for patient selection and trial enrichment. What have we learned from the results obtained in the last years with targeted agents? When a new drug has been administered, either as a single agent or in addition to chemotherapy in a study population not selected by any biomarker, most trials have produced negative results, while in a small minority of cases a statistically significant benefit has been demonstrated. This benefit, however, consisted -- at best -- of a small or moderate absolute prolongation of overall survival. On the other hand, examples of a greater absolute benefit obtained with the use of targeted agents based on a biomarker-driven patient selection are constantly increasing. Biomarkers provide the possibility to use tumor and patient characteristics to integrate an accurate predictor of efficacy with a specific mechanism based therapy, guiding the selection of treatment for each individual patient. In particular, a validated predictive marker can prospectively identify individuals who are likely to have a positive clinical outcome from a specific treatment. Our study recognizes these issues and proposes to develop and validate biomarkers for a biomarker- driven patient selection and trial enrichment in the implementation of Hsp90 inhibitors into the treatment of women with triple-negative breast cancers.
|Speranza, Giovanna; Anderson, Larry; Chen, Alice P et al. (2018) First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile. Invest New Drugs 36:230-239|
|Joshi, Suhasini; Wang, Tai; Araujo, Thaís L S et al. (2018) Adapting to stress - chaperome networks in cancer. Nat Rev Cancer 18:562-575|
|Guo, A; Lu, P; Lee, J et al. (2017) HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene 36:3441-3449|
|Weidenauer, Lorenz; Wang, Tai; Joshi, Suhasini et al. (2017) Proteomic interrogation of HSP90 and insights for medical research. Expert Rev Proteomics 14:1105-1117|
|Rodina, Anna; Wang, Tai; Yan, Pengrong et al. (2016) The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538:397-401|
|Chiosis, Gabriela (2016) Editorial (Thematic Issue: Heat Shock Proteins in Disease - From Molecular Mechanisms to Therapeutics). Curr Top Med Chem 16:2727-8|
|Chiosis, Gabriela (2016) Editorial: Heat Shock Protein in Disease - From Molecular Mechanisms to Therapeutics. Curr Top Med Chem :|
|Goldstein, Rebecca L; Yang, Shao Ning; Taldone, Tony et al. (2015) Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J Clin Invest 125:4559-71|
|(2015) Voices of chemical biology. Nat Chem Biol 11:378-9|
|Taldone, Tony; Kang, Yanlong; Patel, Hardik J et al. (2014) Heat shock protein 70 inhibitors. 2. 2,5'-thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and 3-(phenylthio)pyridines as reversible binders to an allosteric site on heat shock protein 70. J Med Chem 57:1208-24|
Showing the most recent 10 out of 31 publications