Targeting Breast Cancer Stem Cells Clinical Trials

Tumor Dormancy.  In collaboration with Sendurai Mani (MD Anderson) and Herbert Levine (Northeastern) laboratories: There is accumulating evidence that tumor cells may disseminate to distant sites during early stages of tumor progression. These disseminated tumor cells (DTCs) may remain dormant or proliferate to form clinically significant metastases. The natural history of breast cancer (BC) reflects these processes with almost all deaths due to metastatic progression. Approximately 85% of BC patients have DTCs in their bone marrow (BM) at the time of initial diagnosis. Although these women have a higher risk of recurrence than those without DTCs, most of these women will not recur. However, after a long latency period, DTCs will grow out and form fatal metastasis in a subset of these women. Currently, there is no way to determine which women with DTCs will progress, and there are no effective strategies to reduce or prevent recurrence. The Wicha lab has established a multi-institution collaboration with the Mani and Levine labs to addresses the biology of tumor cell dormancy and the exit out of dormancy and assesses the intrinsic and extrinsic factors regulating dormancy maintenance and reactivation in the BM microenvironment. This collaboration seeks to study the intrinsic properties of dormant DTCs, including their “stem-like” state as well as the role of the epithelial-mesenchymal transition (EMT)-mesenchymal-epithelial transition (MET) cell state in controlling tumor dormancy and reawakening, and determine how the BM microenvironmental niche regulates these states.

Plasticity. In collaboration with Nancy Papalopulu (University of Manchester) laboratory: Estrogen receptor positive breast cancer, while targetable with hormone therapies, presents a significant clinical challenge due to the constant rate of recurrence of disease after cure. The constant rate of recurrence is thought to be caused by the stochastic reactivation of dormant disseminated tumor cells but the mechanisms of dormancy and reactivation are not known. The collaboration between the Wicha and Papalopulu labs seeks to study the plasticity of cancer stem cells which is required for entrance and exit from dormancy using live imaging reporter systems, cancer stem cell assays, and developing systems for studying dormancy both in vitro and in vivo.

Notch Inhibition. In collaboration with Baylor College of Medicine and the Dana-Farber Institute, we launched one of the first clinical trial designed to target breast CSCs. This trial, sponsored by Merck, utilized a gamma secretase inhibitor to block Notch signaling in breast cancer stem cells. A total of thirty-five patients were treated on this Phase I protocol. We demonstrated that this stem cell inhibitor could be safely administered with little added toxicity. Furthermore, by obtaining biopsies in a subset of patients before and after therapy, we demonstrated that this Notch targeting agent resulted in reduction of stem cell content in biopsies obtained after therapy. A manuscript describing this works is in preparation.

Targeting the IL-8 receptor CXCR1. Our lab demonstrated a key link between inflammation, tissue damage and CSCs is mediated by the cytokine IL-8. We demonstrated that cytotoxic chemotherapy resulted in secretion of this cytokine which stimulated adjacent cancer stem cells through the IL-8 receptor CXCR1. A small molecule inhibitor, Repertaxin, which blocks CXCR1, was able to specifically target breast CSCs in xenograft models. We have entered into a licensing agreement with Dompe Pharmaceuticals from Milan, Italy to utilize their small molecules CXCR1 inhibitor in a clinical trial to target breast CSCs. This trial represents the first of its kind, designed to specifically attack CSCs in patients by targeting the interaction of these cells with the microenvironment. The trial opened in 2011 at Johns Hopkins and in Jan 2012 at the UMCCC under the direction of Anne Schott. To date four patients have been accrued to this trial.

Hedgehog plus Notch Inhibition. Based on our preclinical work, we launched a clinical trial in 2010 combining Notch inhibition with Hedgehog inhibition to target breast CSCs. This trial is being done in collaboration with Dr. Patricia LoRusso at Karmanos Cancer Institute (KCI).  To date we have received more than four dozen samples and biopsies from KCI representing multiple tissues, pre and post-treatment from more than one dozen patients.  We have also recently been able to accrue several patients at Michigan. The Ravitz Phase I Center is conducting Hedgehog analyses, while Dr. Miele at the University of Mississippi Medical Center
will perform the Notch analyses on the patient samples.

HER-2 and Akt in CSCs. Over the past few years we published several papers demonstrating that the HER-2 gene (amplified in 20% of breast cancer patients) is an important regulator of breast CSCs. We have shown that resistance to HER-2 may be mediated by deletion of the PTEN gene which activates Akt. Based on this, we have designed a novel phase I clinical trial combining trastuzumab (Herceptin) with an Akt inhibitor. This trial has been approved by CTEP at the National Cancer Institute and has also received funding from the Department of Defense Breast Cancer Research Program. Karmanos has written the protocol necessary to accrue patients who may benefit from this novel therapy. We anticipate initiating this clinical trial later this year or next.

PARP Inhibition plus Chk-1/2 Inhibition. A Phase Ib trial combining a PARP inhibitor with AZD7762 (Chk1/2 kinase inhibitor) was approved by AstraZeneca in 2011. The protocol was approved at KCI in May 2012 and the trial began accruing in June 2012. The PARP compound is being given orally twice daily; AZD7762 intravenous weekly. Both agents will be escalated in respective cohorts. The patient population consists of women with advanced TNBC. Tissue will be collected at baseline and at the end of cycle 1 of the combination. The PK profiles of the drugs will be assessed, alone and in combination. In addition, the feasibility of evaluating levels of select PD BCSC differentiation biomarkers in the Chk signaling pathway and related to DNA damage repair (e.g. PARP, Chk1&2, gamma-H2AX, Caspace3, RAD51, CD44/CD24, ALDH), and the percentage of BCSCs in BC biopsies will be assessed before and after treatment. TES will be profiled on both the CSC and tumor bulk cells. KCI holds the IND with the FDA. Patient recruitment will include KCI, UM and Dana Farber Cancer Institute. Samples will be analyzed at VARI/TGen, Baylor, and UM.

IL-6R Inhibition. A new CSC trial is envisioned in an effort to overcoming trastuzumab resistance by blocking an inflammatory feedback loop using anti-IL6 antibody tocilizumab. A paper in press in Molecular Cell describes the pre-clinical studies which support this model. Based on this pre-clinical work, we are now working with Genentech to design a study using the IL6-R antibody tocilizumab to treat women with trastuzumab refractors HER2-positive breast cancer. We anticipate that this study will open later this year.

Support from SU2C has allowed us to advance our basic studies and launch clinical trials based on our most promising pre-clinical findings. As a result, we are performing some of the first clinical trials designed to target CSCs. Our prior research has demonstrated that these cells drive tumor growth and metastasis. Consequently, CSC therapies have the potential to significantly improve the outcome for women with advanced breast cancer.