Targeting tumor-initiating niche to overcome chemoresistance
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Non-technical overview of the research topic and relevance to breast cancer:
 For women presenting with triple-negative breast cancer (TNBC), it is well established that in the absence of
 estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2),
 treatment options for TNBC patients are limited to standard chemotherapy. Despite having a good initial
 response to chemotherapy, TNBC patients present significant higher rates of metastasis relapse and a worse
 prognosis than those presenting with non-TNBC. Studies show that tumor microenvironment, especially the
 extracellular matrix niche (or tumor associated “soil”) surrounding tumor-initiating cells, play an important role
 in tumor reinitiation upon chemotherapy. However, no therapies targeting such tumor-associated “soil” have
 been developed to overcome chemoresistance. The proposed research aims to test a therapeutic approach to
 specifically target the tumor-associated “soil” to overcome chemoresistance in TNBC patients.
 
 
 The question(s) or central hypotheses of the research:
 Our proposed research aims to test the hypothesis that tumor-associated “soil” in TNBC tumors promote
 chemoresistance and to determine whether therapeutic targeting of one critical protein named periostin in
 tumor associated “soil” could enhance chemotherapy responses and improve survival in TNBC patients.
 
 
 The general methodology:
 In Aim 1, we will further examine periostin expression in TNBC patient tumor samples before and after
 neoadjuvant chemotherapy collected via the I-SPY 2 clinical trial to determine the value of periostin as an
 effective marker to predict chemoresponsiveness in TNBC patients. In Aim 2, we plan to use TNBC tumors
 generated from human cell lines and human patient-derived xenografts to test whether applying periostinblocking
 antibody could improve chemoresponses in mice. In Aim 3, we aim to understand how periostin
 promotes chemoresistance in TNBC.
 
 
 Innovative elements of the project and potential impact:
 The proposed research aims to address a critical issue in breast cancer treatment – chemoresistance. This is
 particularly relevant to triple-negative breast cancer, for which chemotherapy is the only available treatment
 option. Most previous efforts in overcoming chemoresistance have been focused on proteins inside tumor
 cells that regulating cell death and drug transport. The proposed research tests the novel concept that unique
 changes in tumor associated “soil” upon chemotherapy contribute to chemoresistance by supporting the
 expansion of tumor-initiating cells upon chemotherapy treatment. Our preliminary studies have identified one
 such unique protein that is specifically upregulated upon chemotherapy and promotes chemoresistance in
 TNBC xenografts. Therefore, our study could demonstrate the immediate clinical use of periostin as a
 predictive marker for chemoresponsiveness in TNBCs. This could aid in identifying TNBC patients who will
 become chemoresistant and may benefit from the use of novel therapies in addition to standard chemotherapy
 at diagnosis.
 
 
 Therapeutic targeting of molecules in tumor-associated “soil” has been challenging partially due to critical roles
 these proteins play in normal cell function. Our preliminary data indicate that upregulation of a tumor-specific
 form of the periostin protein upon chemotherapy could provide a therapeutic window to target with minimum
 toxicity. We will test a novel antibody against this specific isoform of periostin to explore its therapeutic
 potential in reducing chemoresistance and improve long-term survival in TNBCs. If the proposed research is
 successful, the next step is to further develop a humanized version of the periostin antibody and to test in
 clinical trails the utility of blocking a specific isoform of periostin in reducing chemoresistance in TNBC patients.
 It is our hope that combining periostin blockade with chemotherapy could improve metastasis free and overall
 survival in TNBC patients.
 
 
 TNBCs affect younger women more frequently and are more prevalent in African-Americans, who are three
 times more likely to present with TNBC than Caucasian women. Therefore, the proposed therapy could also
 potentially improve this cancer disparity issue in TNBC.