Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity

Abstract

One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current advancements in the development of multitarget therapeutics that have shown promising results in clinical and preclinical studies when used alone or in combination with traditional regimens of surgery, chemotherapy, and/or radiation.

Keywords:

• breast cancer
• alternative therapy
• drug resistance
• cancer stem cells

Acknowledgments

This work was supported in part by grants to MR Szewczuk from the Natural Sciences and Engineering Research Council of Canada, private sector cancer funding from the Josefowitz Family to MR Szewczuk and Encyt Technologies, Inc.

Author contributions

All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

M Sambi is a recipient of the Queen’s Graduate Award (QGA). S Haq is the recipient of QGA and the 2016 Ontario Graduate Scholarship (OGS). F Haxho was the recipient of the QGA, the Graduate Entrance Tuition Award (GETA), the Natural Sciences and Engineering Research Council of Canada (NSERC) Alexander Graham Bell Canada Graduate Scholarship-Master’s (CGS M), and now the Vanier Canada Graduate Scholarship. V Samuel is the recipient of the Queen’s University Principal’s Scholarship and the Board of Governor’s Award. The authors report no other conflicts of interest in this work.