Clinical Implications of Targeting Cancer Stem Cells in MBC

By Joan Mancuso

In working hard to develop systemic treatments for breast cancer, scientists are rigorously conducting research on targeting our immune system. Along with that, work by Dr. Max Wicha has shed light on understanding how cancer stem cells (CSC) contribute to the growth and spread of tumors, as well as how these cells interact with the immune system. As a result of his research, he is now conducting breast cancer clinical trials using compounds to target CSC of the breast.

At the San Antonio Breast Cancer Symposium (SABCS) in December, Dr. Wicha received the American Association for Cancer Research’s Distinguished Lectureship Award in Breast Cancer Research to recognize his outstanding contribution to science in studying CSC. Dr. Wicha is Madeline and Sidney Forbes Professor of Oncology and Founding Director Emeritus of University of Michigan Comprehensive Cancer Center. Besides directing a cancer laboratory that studies CSC of the breast, he is also a clinician who actively treats breast cancer patients and a co-founder of OncoMed Pharmaceuticals, Inc.

Overcoming cancer therapy resistance

Cancer cells with stem-cell-like properties can resist chemotherapy and radiotherapy and “self-renew,” leading to a population of left-behind cancer cells that continue to grow and spread, Dr. Wicha said during his presentation. Besides CSC and the immune system, scientists in his lab are also studying the affect of inflammatory pathways on this growth and dissemination process.

Cancer cells can change from one state into another, which seems to enable them to resist treatments after they make that transition, Dr. Wicha said. He noted that scientists might have to develop drugs to destroy both cell states, to effectively destroy CSC. However, he also emphasized that a combination of anti-CSC therapeutics, chemotherapy (including targeted drugs) and immunotherapy will mostly likely be the ingredients necessary to effectively eradicate cancer.

Clinical trial options

Dr. Wicha is currently involved in clinical trials using various anti-cancer drugs. A phase Ib pilot study with 33 HER2-negative metastatic breast cancer (MBC) patients showed good results, leading to a 200 patient, multinational, randomized clinical trial now underway. In the first trial the anti-inflammatory regulator reparixin was combined with Taxol (paclitaxel). The subsequent trial is now comparing that drug combination to Taxol alone in MBC. (A double-blind study of paclitaxel in combination with reparixin or placebo for metastatic triple-negative breast cancer (FRIDA)). https://clinicaltrials.gov/ct2/show/NCT02370238?term=NCT02370238&recrs=a&rank=1 A double-blind clinical trial helps to ensure that enrollees and their oncologists will have an unbiased assessment of side effects because they do not know who received the experimental drug.

Everyone in this clinical trial receives Taxol, but only some of the enrollees receive reparixin, with the remainder of the enrolled participants receiving a placebo. Today, no enrollees in clinical trials ever receive only a placebo. That would be unethical. Everyone receives the standard-of-care treatment. Enrollees are protected by the strict criteria of institutional review boards, who review the protocols of clinical trials being conducted at their institution.

In an upcoming phase I clinical trial, MBC patients resistant to anti-HER2 therapies (Herceptin, Perjeta or Kadcyla) will receive a combination of an already approved anti-inflammatory, rheumatoid arthritis drug (tocilizumab) in combination with Herceptin, to determine the best dosage level of tocilizumab (for further information, contact Drs. Monika Burness and Anne Schott of University of Michigan Comprehensive Cancer Center).

Clinical trials with compounds targeting CSC and the associated pharmaceutical companies include:

1. Phase 1b: A study of ventictumab (OMP-18R5) in combination with paclitaxel in locally recurrent or metastatic breast cancer. https://clinicaltrials.gov/ct2/show/NCT01973309?term=NCT01973309&rank=1 HER2-negative MBC. OncoMed.

2. Phase 1b: A study of demcizumab plus pembroluzumab in locally advanced or metastatic solid tumors. https://clinicaltrials.gov/ct2/show/NCT02722954?term=NCT02722954&rank=1) OncoMed. Pembroluzumab (brand name, Keytruda) is an FDA-approved immunotherapy originally approved to treat metastatic melanoma. The drug is now also used to treat other cancers, and recently, the FDA approved Keytruda for any advanced cancer with specific genetic features. That is the first time that the FDA has given approval to a cancer drug based solely on the presence of genetic features rather than organ type, which can improve MBC patients’ access to Keytruda.

3. Phase I: Defactinib combined with pembroluzumab and gemcitabine in patients with advanced cancers. https://clinicaltrials.gov/ct2/show/NCT02546531?term=NCT02546531&rank=1 Verastem Inc. Gemcitabine is the generic name of Gemzar, which is used to treat MBC.

If patients have questions about any of these clinical trials, they can always ask their oncologist, talk to clinical trial personnel through contact information found on clinicaltrials.gov for each trial, and/or contact the pharmaceutical company directly.

Patients who are not located in an area of a clinical trial may still be able to participate. In some instances, clinical trial staff may require them to go only once to the trial site but otherwise visit with their local oncologist for follow-up scans and blood tests. That would depend on the clinical trial and arrangements that could potentially be made with the staff at each trial site, if at all.


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