Low-Dose Regularly Timed Chemotherapy May Keep Some Resistant Cancers in Check

MedicalResearch.com Interview with:

Kelvin K. Tsai, MD, PhD Associate Investigator and Attending Physician Laboratories for Tumor Aggressiveness and Stemness National Institute of Cancer Research, National Health Research Institutes Associate Professor and Principal Investigator Laboratories of Advanced Molecular Therapeutics Graduate Institute of Clinical Medicine College of Medicine, Taipei Medical University, Taiwan

Dr. Kelvin K. Tsai

Kelvin K. Tsai, MD, PhD
Associate Investigator and Attending Physician
Laboratories for Tumor Aggressiveness and Stemness
National Institute of Cancer Research, National Health Research Institutes
Associate Professor and Principal Investigator
Laboratories of Advanced Molecular Therapeutics
Graduate Institute of Clinical Medicine
College of Medicine, Taipei Medical University, Taiwan

MedicalResearch.com: What is the background for this study?

Response: Human cancer is a complex organ consisting of a heterogenous collection of cancer cells and stroma cells. Many solid tumors such as breast cancer and pancreatic cancer are characterized by a pronounced stromal fibrosis termed desmoplasia. Studies showed that systemic chemotherapy can target not only cancer cells but also the stromal fibroblasts, which may have significant impacts on the treatment response in desmoplastic cancers.

We set out to study whether and how traditional “maximum tolerated dose (MTD)” chemotherapy affects the tumor fibroblasts and thereby modulates the treatment response, and if so how this therapy-induced stroma perturbation can be avoided or attenuated.

MedicalResearch.com:? What are the main findings?

Response: Our research identified that traditional  maximum tolerated dose chemotherapy activates the stromal fibroblasts to secrete various “ELR-motif-positive chemokines”, which act to convert the cancer cells into a highly invasive and resistant subset of less differentiated cells called “tumor-initiating cells (TICs)” or “cancer stem cells”.

As such, these therapy-altered fibroblasts can paradoxically promote cancer growth and metastasis in certain preclinical models of desmoplastic breast and pancreatic cancers. This inadvertent stromal response can be largely tempered by altering the dosing schedule of chemotherapy to “low-dose metronomic” regimens.

MedicalResearch.com: What should readers take away from your report?

1. Systemic chemotherapy has a significant impact on the tumor stroma.
2. The treatment response of highly fibrotic cancers depends to a significant extent on the reaction of stromal fibroblasts.
3. Low-dose metronomic chemotherapy has minimal stimulatory effects on stromal fibroblasts and thereby exerts an enhanced anti-tumor efficacy especially in desmoplastic cancers.
4. Our research illustrates the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

1. Our study may motivate more clinical trials examining the effects of low-dose metronomic chemotherapy on the tumor stroma and TICs and its anti-tumor efficacy especially in desmoplastic cancers.
2. Our study may help the identification of the cancer patients who will benefit from metronomic chemotherapy to guide the design of tumor-tailored chemotherapy regimens.
3. Targeting the chemokine paracrine signaling mediated by CAFs may provide a new avenue for improving the therapeutic outcome in desmoplastic cancers.

MedicalResearch.com: Is there anything else you would like to add?

Response: MTD chemotherapy also profoundly affects other components of the tumor stroma such as the immune cells, which may antagonize the treatment efficacy.

The effects of metronomic chemotherapy on tumor immunity demands further investigation.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Chan et al. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J. Exp. Med, November 2016 DOI: 10.1084/jem.20151665

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