Our translational research team has studied solid tumor malignancies including pancreas, colon, melanoma and prostate cancer. Our laboratory has also served as the lead site for correlative studies associated with several pancreatic cancer clinical trials, and for a biobank for tissue and fluid for patients with gastrointestinal malignancies since 2006. Of 72 total publications, 27 involve human samples, 15 of which involve Phase I clinical trials, or pre-clinical data that led to these trials. Many studies represent first in man combination therapy against cancers, including pancreatic cancer where correlative studies for these trials took place in our laboratory. Our group thrives on collaborative integration with clinical investigators in a multi-disciplinary setting. Our group has made advances in understanding immune suppression in cancer, the Jak/STAT signaling pathway in the tumor stroma, and in limiting chronic inflammation as a mediator of carcinogenesis.
Our overall goal is to maintain a highly-collaborative research program focused on translating novel immune and targeted therapies into clinical trials for patients with gastrointestinal malignancy. Our initial focus has been to pursue combined therapeutic approaches targeting cytokines and pathways derived from the tumor and stroma to enhance the efficacy of immunotherapy. Of particular interest will be signal transduction pathways that have a shared role in promoting tumor cell growth or metastasis and immune suppressive cell expansion.
Priority research areas
To determine how targeting the stromal components of gastrointestinal cancers can be leveraged to enhance immunotherapy, and translate them into clinical trials.
Our laboratory is expanding on our prior observations that IL-6 is a poor prognostic indicator in patients with metastatic pancreatic cancer (Farren et al., Clin Cancer Res, 2016) and may be derived from tumor stroma as a means to facilitate immune evasion by the cancer (Mace + T cell dependent anti-tumor efficacy (Mace et al., Gut, 2016). Further studies funded by an NCI R01 grant (PI: Lesinski; 1R01CA208253-01) will delineate the mechanism for anti-tumor efficacy in vivo and pursue this and similar concepts in the setting of early phase clinical trials. The role of IL-6 and its downstream signaling events are of great interest to our group both in the setting of advanced cancer, as well as during inflammatory conditions like pancreatitis that increase risk of cancer. Thus, targeting IL-6/Jak-STAT signaling in pancreatic inflammation is the topic of a funded NIH R21 grant (co-PI: Lesinski/Ostrowski; 1R21AI124687-01). We also maintain a collaborative relationship with Surgical and Medical Oncology that can continue to facilitate this research to discover new therapeutic targets and validate previously identified genes and pathways within the stroma. The role of the pancreatic stroma in carcinogenesis is quite controversial, and these studies will continue to add to our understanding into the dynamic process that occurs within the microenvironment.
To understand how conventional therapy approaches (radiation, chemotherapy) influence specific immunologic factors that can be targeted therapeutically.
In theory, this approach could potentially allow for improving antigenicity of tumors that were traditionally viewed as immunologically non-responsive (i.e. microsatellite stable colorectal cancer). To date, we have little if any understanding how conventional chemotherapy or radiotherapy is modulating actionable immune biomarkers either systemically or within the tumor. These approaches may unmask neoantigens or modulate various immune suppressive mechanisms that could be leveraged therapeutically to enhance the efficacy of immune-based therapy. In line with this research, our laboratory currently is the lead site for correlative studies associated with a national, phase II clinical trial of FOLFOX chemotherapy combined with Pembrolizumab in colorectal cancer. Other interests of our group are in moving beyond the PD1/PD-L1 and CTLA4 axis, to explore how alternative immune checkpoint molecules can be leveraged in combination with conventional and targeted therapy.
Use of natural products to alter the immune response during chronic inflammation and carcinogenesis.
It is well recognized that chronic inflammation plays a major role in carcinogenesis. This concept strongly implies that dysregulated immunity occurs at even the earliest stages of tumor development. We believe that neutralizing aberrant inflammatory responses may be a viable first line of defense against cancer. One very interesting approach to limiting inflammation involves dietary intervention with foods possessing known chemopreventive activity. Over the past four years, we have collaborated across disciplines investigating how dietary intervention with whole foods, including soy, black raspberries and mangosteen, can modulate immune function (Lesinski et al., Cancer Prev Res, 2015). These fascinating projects have led our group to pursue the hypothesis that the anti-inflammatory properties of bioactive components within foods can impact carcinogenesis. In particular, we are interested in how these foods or their bioactive components modulate expansion of myeloid cells in response to inflammatory stimuli or in the setting of established cancer. We are delineating signal transduction pathways (i.e. STAT3, MAPK) altered by candidate bioactive compounds in these foods (Mace et al. Cancer Immunol Immunother, 2014). Our preliminary work has led to an NCI R01 grant on soy isoflavones as immune modulators in prostate cancer (PI: Lesinski; 1R01 CA169363-01). This project will provide critical data supporting future studies to test whether these dietary interventions can modulate the biologic and clinical response to immune-based therapies, including vaccines or cytokines.