Our laboratory studies complex cell-cell and signaling pathway connectivity interactions with the aim of improving lymphoma prognosis and treatment through:
- Development of new and innovative targeted cancer therapeutics.
- Investigation of biologic aspects of the immune system through novel microfluidic and single cell technology.
- Discovery of "omic" biomarkers of efficacy and resistance to cancer therapeutics.
Within these areas, we examine B-cell lymphoma, T-cell lymphoma, and Hodgkin lymphoma exploiting several tumor models including cell lines, primary/patient-derived samples, xenograft, and PDX models. In addition, we leverage a Systems Biology approach where disciplines such as mathematics, genomics, and classical biology come together to help answer important biological questions.
Development of innovative and novel targeted cancer therapeutics in lymphoma
Our lab has examined the biologic and prognostic importance and potential treatment relevance of microRNA (miRNA) in lymphoma. This work includes the development of a multi-miRNA based therapy concept, which intends to utilize miRNAs that act as molecular scissors to weed out cancer-associated proteins. We believe that a collective repression of the tumor-associated miRNAs, easily detectable in the circulating cells (peripheral blood), will tip the scales to growth inhibition for lymphoma patients (Figure 1). In addition, patterns of circulating miRNA that are readily detectable in the blood may serve as potential prognostic markers for patients with lymphoma to be harnessed as a form of "liquid biopsy".
Investigation of biologic aspects of the immune system through novel microfluidic and single cell technology
Cancer cells develop several strategies to evade detection and killing by immune cells and the existence of phenotypically heterogeneous cell populations within the tumor microenvironment add further complexity to treatment response.
One focus of our lab is to understand why immunotherapy with rituximab (anti-CD20) fails to trigger immune system response in >50% of B cell lymphoma patients. Additionally, we are investigating a novel NK cell-based therapy design to facilitate B cell lymphoma killing.
We are also actively engaged in determining the benefit of using anti-TIM3, anti-LAG3 and anti-PD1 based immunotherapy both as mono or combinational therapeutic approach for lymphoma treatment.
Given that single cell assays allow for comprehension of individual cellular behaviors and tumor-immune cell interaction, in the presence and absence of drugs, our lab has collaborative ongoing research to develop innovative microfluidics-based single cell assays. We believe that this approach will facilitate prediction of patient's response and discover novel drug combinations.
This research is funded by NIH with a recent multi-PI R33 grant award, 1R33CA223908-01, in collaboration with engineering investigators at Northeastern University.
Discovery of "omic" biomarkers of efficacy and resistance to cancer therapeutics
Through comprehensive systems biology approaches, our lab has discovered the existence of biologically heterogeneous responses to treatments with various targeted cancer therapeutics, such as ixazomib. We identified potential drug targets that could be used in rational combinatorial therapy to enhance cell death as well as to harness these systems biology findings for pertinent biomarkers of drug activity and resistance. (Figure 2)
We also utilize unique cancer models to study novel therapeutics and identify predictive associated biomarkers. The canine model, for instance, is highly appealing for cancer research due to a fully intact immune system, similar clinico-pathologic features of the disease, relatively similar body size and pharmacokinetic properties, and with a lifespan that allows lifelong follow-up over a markedly shorter timeframe. We recently defined detailed morphologic and immunohistochemistry data in canine TCL (cTCL) to determine prevalent mutations that could have relevant clinical significance in humans (Figure 3) (accepted for publication, Oncotarget, April 2018).
We believe that omics-based applications and connectivity mapping of signaling pathways represent a technological resource to further expand our knowledge of the complexities of cancer and that may significantly accelerate drug discovery.