Research

Overview

The tumor microenvironment has long been identified as a major factor influencing treatment resistance of cancer to conventional anticancer therapies. In addition it is now well recognized that the tumor microenvironment plays a critical role in neoplastic cell initiation, malignant progression, and metastatic spread of tumor cells. However, the very characteristics of the tumor microenvironment that lead to therapy resistance also can provide unique treatment opportunities.

A major focus of this laboratory is the development and assessment of novel anticancer treatment strategies. One approach seeks to target unique conditions of the tumor microenvironment which may be exploited for therapeutic gain. A primary target has been tumor hypoxia; a consequence of the abnormal and inadequate development of blood vessel networks in tumors. Therapeutic approaches being pursued include hypoxic cell radiosensitizers, bioreductive drugs, and non-drug strategies such as aerobic exercise to improve tumor pathophysiology. Another strategy is focused on directly targeting the root of the abnormal tumor microenvironments; the tumor blood vessel network. This research involves both anti-angiogenic therapies that aim to interfere with new tumor blood vessel formation and vascular disrupting approaches that directly damage the tumor’s blood supply. Since tumor cells avoid detection from the immune system by expressing checkpoint proteins on their surfaces, targeting these proteins can enhance the immune response of the tumor. The overarching goal of these preclinical investigations is to develop and evaluate novel treatment strategies designed to impede metastasis because the dissemination of tumor cells to distant sites is responsible for nearly 90% of all cancer deaths.

 


Current Laboratory Projects

Tumor Vasculature/Imaging
Osteosarcoma
Cathepsin L Targeting In Metastatic Disease
Inhibition Of Src And C-Met Signaling Pathways
Inhibiting mTOR Signaling
Targeting The Tumor Microenvironment
Impact Of Exercise On Tumor Physiology
Cancer Immunotherapy

These laboratory investigations utilize a variety of human and rodent preclinical cancer models, with particular emphasis on models of prostate, breast, kidney, and colorectal cancer as well as osteo- and fibro-sarcoma. The research emphasizes translational medicine in oncology with the ultimate goal developing and advancing new treatment strategies for the clinical management of cancer.

 


Tumor Vasculature/Imaging

Tumor microvasculature is characterized by abnormalities in structure, function and organization that lead to inhibited blood flow and oxygen delivery. These conditions can promote the development of a more aggressive cancer while also inhibiting the effective delivery and efficacy of conventional cancer treatments.  In order to better understand the relationship between tumor vessel morphology, blood flow and oxygenation, wide-field hyperspectral imaging of hemoglobin saturation and first pass fluorescence imaging of blood transit time of tumors in the mouse dorsal skinfold window chamber model are used to characterize the effects of microvessel structure and connections on oxygen transport. This combination imaging technique is being applied to study the real-time development and responses of tumor microvasculature to various anticancer therapies or following structured aerobic exercise.

Osteosarcoma

Cancers that spread to bone, or arise in bone, such as prostate cancer and osteosarcoma, cause morbidity due to abnormal bone remodeling, bone loss, increased risk of fractures, decreased mobility and severe pain. This project involves characterizing tumor progression and the effects of molecular targeting agents on signaling cascades associated with growth and metastasis. Radiotherapy is commonly used in multimodal treatment regimens for these cancers, so studies will be performed to determine if the addition of promising targeted agents results in improved outcomes, using both cell culture and mouse xenograft experiments. Cancer cells expressing Green Fluorescent Protein and luciferase are used to track to track cancer progression and spread to secondary sites.

Cathepsin L Targeting In Metastatic Disease

It is now well recognized that proteolytic enzymes play a crucial role in metastatic progression. Proteases facilitate several aspects of the metastatic cascade including tumor cell detachment, invasion through extracellular and interstitial matrices and basement membranes, intravasation and extravasation across the capillary/lymphatic system and activation of latent growth factors. Our lab focuses on the role of cysteine protease cathepsin L and its intervention in metastatic models of prostate and breast cancer. Specifically, we are actively investigating the anti-invasive and anti-angiogenic properties of a series of small molecule cathepsin L inhibitors in several in-vitro and in-vivo metastasis models.

Inhibition Of Src And C-Met Signaling Pathways

Metastasis is the most common cause of cancer-related death. In order for a tumor cell to metastasize, it must complete a number of steps, including migration, invasion, survival, angiogenesis, and growth. Selective up-regulation of signaling pathways associated with proliferation, migration and invasion, such as the Src pathway and the c-Met/HGF, can result in the increased ability of tumor cells to metastasize. Strategies that interfere with such critical signaling in cancer cells are being actively pursued at the molecular and cellular level. To maximize antitumor and antimetastatic activity the judicious application of such agents in combination is being investigated.

Inhibiting mTOR signaling

mTOR protein kinase is an oncoprotein that is often dysregulated in human cancers. Classic mTOR inhibitors such as rapamycin have shown some clinical benefits however both innate and acquired resistance will inevitably occur following treatment with this agent; consequently significantly weakening its therapeutic potential. The goal of this research project is to understand the mechanisms of mTOR inhibitor-mediated resistance and further to identify novel second generation agents and innovative treatment strategies aimed at overcoming such resistance. These studies could ultimately provide critical insights that would allow future application of mTOR-based interventions in the clinic.

Targeting The Tumor Microenvironment

Laboratory and clinical evidence indicating that inadequate blood vessel networks in tumors can lead to areas within tumors where cancer cells exist at lower than normal oxygen levels. The presence of such hypoxic cells in tumors can lead to resistance to radiotherapy and reduced chemotherapeutic agent efficacy, and may alter tumor progression and metastatic frequency. To overcome such treatment resistance, novel anticancer agents that are activated to cytotoxins only under hypoxic conditions are being evaluated. Another approach is to attack the supportive blood vessel network of tumors directly using agents that either inhibit the tumor’s ability to establish new vessel growth (antiangiogenic therapies) or directly damage existing tumor blood vessels (vascular disrupting agents).

Impact Of Exercise On Tumor Physiology

Intratumoral low oxygen levels, a common occurrence in several cancers including breast cancer, is a strong prognostic indicator of poor clinical outcome. Indeed, hypoxia in solid tumors is a major contributing factor in resistance to conventional anticancer therapies such as radiotherapy and chemotherapy. In addition, by causing genomic instability and transcriptional reprogramming, hypoxia promotes tumor aggressiveness. Hence, there is significant interest in developing novel strategies to improve the oxygenation state of tumors in order to improve the efficacy of anticancer treatments. Our laboratory is exploring the possibility that aerobic exercise such as the use of treadmill running may improve tumor oxygenation, perfusion and vascularity to such an extent that it may increase radiation therapy efficacy.

Cancer Immunotherapy

Immune checkpoint molecules ensure appropriate immune function by modulating T-cell activation. Tumors can escape detection from the immune system by expressing large amounts of checkpoint proteins such as programmed cell death ligand-1 (PD-L1) on their cell surface. PD-L1 and PD-1 (a checkpoint protein on T-cells) provide important targets to help reactivate the immune system. Possible approaches to further improving treatment efficacy include using combination approaches involving immunotherapeutic agents targeting different pathways, combining checkpoint inhibitors with small-molecule targeted therapies, or the addition of immunotherapeutic approaches to conventional anticancer therapies such as radiation or chemotherapy.