Breast cancer remains one of the most frequently diagnosed of all cancers, and a leading cause of death among women. As such, there is still a critical need to increase the efficacy of treatments for breast cancer patients. Transplantation of autologous adipose tissue is an accepted treatment to repair defects in breast shape after lumpectomy. Our unique approach will utilize the autologous adipose tissue as a drug reservoir by preloading the transplant with glitazones, FDA approved drugs for the treatment of diabetes-mellitus-2 that have potent anti-cancer properties. The glitazones can induce edema, congestive heart failure and other serious side effects making localized delivery particularly attractive. The glitazone-laden fat will locally produce adiponectin, an anti-cancer adipokine, which will also act to reduce local cancer recurrence through its actions on remnant tumor cells. Thus, the autologous fat will serve two key functions: 1) act as a sustained release drug depot for the glitazones and 2) act as a bioreactor to produce adiponectin at the site of tumor resection. With this approach, any remaining tumor cells will be treated locally by the combined anti-tumor actions of both the glitazone and adiponectin.
In Aim 1 of this application the concentration of glitazone preloaded in adipose tissue that results in the greatest adiponectin and glitazone release and greatest inhibition of tumor cell proliferation in vitro will be determined. Dose escalation studies of glitazone loaded into explanted fat will be performed and the release of adiponectin and glitazone from the cultured fat measured over time. Breast cancer cells will then be treated with the media from the glitazone-loaded adipose tissue, and its effect on cultured breast cancer cell phenotype including proliferation, migration/invasion and incidence of apoptosis in vitro measured.
In Aim 2, the optimized glitazone load will be utilized to evaluate the efficacy of this approach in a mouse model using patient-derived breast cancer tumors. These tumors have the advantage of maintaining the heterogeneity observed in patient tumors, as well as the resistance to chemotherapy. The approach will be tested 1) by transplanting glitazone-fat depots after tumor resection to assess the efficacy of the depot to inhibit recurrence, and 2) by transplanting glitazone-fat depots at time of tumor seeding, to assess its effect on tumor establishment and metastasis. Primary outcomes include tumor growth, cell proliferation, frequency of apoptotic tumor cells, and metastasis. We expect the treated group will have smaller tumors, reduced proliferation, increased apoptosis, and reduced metastasis. This localized treatment will deliver the anti-cancer properties of adiponectin and glitazone over a sustained period of time, with the overall goal of reducing the incidence of recurrent disease. The proposed localized treatment approach utilizes an established technique (fat transfer) and currently available therapeutics (glitazones) to potentially inhibit tumor recurrence following a lumpectomy.
Breast cancer remains a devastating condition and novel therapeutic approaches that improve survival and reduce toxicities are needed. The established technique of autologous fat transplant is co-opted in our approach by pre-loading the fat with glitazone drugs that have anti-cancer properties, prior to transplantation, to the site of breast cancer tumor removal. This could significantly reduce the incidence of local recurrence and has the potential to supplant more toxic systemic therapies.
