Detailed Cancer Ablation

Rethinking Breast Cancer Therapy

The past 100 years has revolutionized the way we treat breast cancer – from radical mastectomies in the early 1900s to immunotherapies a century later. Yet, the basic approach to cancer treatment – surgery, radiation and chemotherapy, has remained largely unchanged. The more stubborn the tumor, the longer and more frequent the interventions, a perpetuating cycle that wears the body down. Modern drugs can reduce this indiscriminate killing of tumor cells by recognizing a single target molecule or mobilizing the patient’s immune system. However, mobilizing the immune system with checkpoint inhibitors can lead to adverse events restricting its use to high-risk patients. resources to an unacceptable level. There is a compelling opportunity to maximize the benefit-to-risk ratio for the treatment of early-stage disease breast cancer.

We have identified a natural, phase-changing polymer, ethyl cellulose, which we use as a scaffold to increase the efficacy, effectiveness and efficiency of breast cancer treatment. Ethyl cellulose is a freely flowing fluid in its soluble form; however, it undergoes a phase change into a biodegradable polymer gel in aqueous media encapsulating the solvent within a hydrophobic shell. We have shown that ethyl cellulose dissolved in ethanol changes from an inert polymer into an active therapeutic that has a local ablation effect. Ethanol disrupts tumor cells in the region in which it is sequestered and can reduce the tumor burden. The ethanol-polymer is visible on ultrasound and therefore readily translatable into a clinical setting.

Ethanol-polymer formulation undergoes a phase change in aqueous media to sequester ethanol in the region of interest in the tissue and this injectable is visible on ultrasound making it translatable to a clinical setting.

Ethanol mediated cell injury promotes the activation of anti-tumor T cells. Certain chemotherapy drugs, such as cyclophosphamide when delivered at low doses can work in tandem with the ethyl-cellulose and ethanol formulation to suppress pro-tumorigenic regulatory T cells. We have shown that local delivery of the ethanol infused polymer, and the systemic delivery of cyclophosphamide elicits a therapeutic effect significantly reducing the metastatic burden. Further the ethanol-polymer formulation coupled with cyclophosphamide recovers tumor response to immunotherapy, resulting in increased overall survival compared to the drug alone. This injectable therapeutic is relevant to populations where treatment is not accessible, and it can be used as an adjunct to boost existing treatments with checkpoint inhibitors.

Ethanol-polymer formulation coupled with cyclophosphamide recovers tumor response to immunotherapy, resulting in increased overall survival compared to the drug alone.

Metabolic imaging of residual disease in Breast Cancer

With the widespread adoption of mammograms for cancer detection, modern research has principally pivoted towards a focus on how to predict recurrence and ultimately to prevent it. Approximately 30% of breast cancer patients lacking any clinical or pathological signs of metastasis have disseminated tumor cells present at the time of their diagnosis. Thus, residual disease at the primary tumor site after therapy could be viewed as a surrogate for micro-metastasis elsewhere in the body that may have evaded the drug and could potentially return as recurrent disease.

Given that recurrence is an important determinant of clinical outcome, it is important to predict and mitigate the presence of residual disease. We have developed a metabolic biomarker imaging technology, the CapCell to report on how tumors reshape their metabolic needs to evade therapeutic stress. Through spatial and longitudinal imaging, the CapCell provides a window into metabolic reprogramming of regression, residual disease and recurrence in patient xenograft and genetically engineered mouse models.

The Capcell is a portable microscope designed to provide uniform illumination for the aspect biopsies, organoids and mammary window chamber tumors. This system can provide wide-field and high-resolution images of biological models

Breast tumors use glucose and fatty acids as nutrient sources. Energy can be generated from either glycolysis or mitochondrial metabolism (oxidative phosphorylation or OX PHOS). CapCell imaging shows that resilient tumor cells survive by switching from a predominantly glycolytic phenotype (2-NBDG) to mitochondrial metabolism (TMRE). Treatment with a drug that inhibits nutrients from fats in the breast tissue reverses this process. This metabolic flexibility and heterogeneity are minimal or absent in treatment responsive disease. This points to the importance of spatial and longitudinal metabolic imaging to inform treatment strategies that can mitigate tumor relapse.

A genetically engineered model (GEM) model of breast cancer shows that there is a shift from glucose dependence to mitochondrial metabolism in when the Her 2 oncogene (causes a subtype of breast cancer) is on (Dox) but this effect is not observed when the oncogene is switched off. Treatment with Etomoxir reverses this effect and improves survival.