TY - JOUR
T1 - Emerging drug targets for triple-negative breast cancer
T2 - a guided tour of the preclinical landscape
AU - Xie, Xuemei
AU - Lee, Jangsoon
AU - Iwase, Toshiaki
AU - Kai, Megumi
AU - Ueno, Naoto T.
N1 - Publisher Copyright:
© 2022 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2022
Y1 - 2022
N2 - Introduction: Triple-negative breast cancer (TNBC) is the most fatal molecular subtype of breast cancer because of its aggressiveness and resistance to chemotherapy. FDA-approved therapies for TNBC are limited to poly(ADP-ribose) polymerase inhibitors, immune checkpoint inhibitors, and trophoblast cell surface antigen 2-targeted antibody-drug conjugate. Therefore, developing a novel effective targeted therapy for TNBC is an urgent unmet need. Areas covered: In this narrative review, we discuss emerging targets for TNBC treatment discovered in early translational studies. We focus on cancer cell membrane molecules, hyperactive intracellular signaling pathways, and the tumor microenvironment (TME) based on their druggability, therapeutic potency, specificity to TNBC, and application in immunotherapy. Expert opinion: The significant challenges in the identification and validation of TNBC-associated targets are 1) application of appropriate genetic, molecular, and immunological approaches for modulating the target, 2) establishment of a proper mouse model that accurately represents the human immune TME, 3) TNBC molecular heterogeneity, and 4) failure translation of preclinical findings to clinical practice. To overcome those difficulties, future research needs to apply novel technology, such as single-cell RNA sequencing, thermostable group II intron reverse transcriptase sequencing, and humanized mouse models. Further, combination treatment targeting multiple pathways in both the TNBC tumor and its TME is essential for effective disease control.
AB - Introduction: Triple-negative breast cancer (TNBC) is the most fatal molecular subtype of breast cancer because of its aggressiveness and resistance to chemotherapy. FDA-approved therapies for TNBC are limited to poly(ADP-ribose) polymerase inhibitors, immune checkpoint inhibitors, and trophoblast cell surface antigen 2-targeted antibody-drug conjugate. Therefore, developing a novel effective targeted therapy for TNBC is an urgent unmet need. Areas covered: In this narrative review, we discuss emerging targets for TNBC treatment discovered in early translational studies. We focus on cancer cell membrane molecules, hyperactive intracellular signaling pathways, and the tumor microenvironment (TME) based on their druggability, therapeutic potency, specificity to TNBC, and application in immunotherapy. Expert opinion: The significant challenges in the identification and validation of TNBC-associated targets are 1) application of appropriate genetic, molecular, and immunological approaches for modulating the target, 2) establishment of a proper mouse model that accurately represents the human immune TME, 3) TNBC molecular heterogeneity, and 4) failure translation of preclinical findings to clinical practice. To overcome those difficulties, future research needs to apply novel technology, such as single-cell RNA sequencing, thermostable group II intron reverse transcriptase sequencing, and humanized mouse models. Further, combination treatment targeting multiple pathways in both the TNBC tumor and its TME is essential for effective disease control.
KW - Triple-negative breast cancer
KW - antibody-drug conjugates
KW - bispecific antibodies
KW - immune cells engineered with chimeric antigen receptors
KW - photoimmunotherapy
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85130874976&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130874976&partnerID=8YFLogxK
U2 - 10.1080/14728222.2022.2077188
DO - 10.1080/14728222.2022.2077188
M3 - Review article
C2 - 35574694
AN - SCOPUS:85130874976
SN - 1472-8222
VL - 26
SP - 405
EP - 425
JO - Expert Opinion on Therapeutic Targets
JF - Expert Opinion on Therapeutic Targets
IS - 5
ER -