Research in the laboratory is focused on various aspects of cancer biology at the molecular level. Specific research areas include (a) Regulation of gene expression at the levels of mRNA stability and translation, (b) Cancer Stem Cells, and (c) mechanism(s) of chemoprevention by dietary factors and its novel derivatives.

• Protease Signatures for Early Cancer Diagnostics and Cancer Therapy Decisions
  • Serine, cysteine, and aspartic proteases are markers for the ability of many cancers to grow and to form metastases. Several serine, cysteine and aspartic proteases are over-expressed by numerous cancer cell lines. Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. This diagnostic assay is comprised of protease-sensitive cleavage sequences for up to 30 proteases, which are used as linkers between two fluorophores (nanoparticles and/or organic or inorganic dyes). Depending on the nanoparticles and dyes used, optical (fluorescence), magnetic (MRI), and x-ray imaging of the tumor location and extension can be performed, together with quantitative determination of the proteases' activities. Similar assays are being developed for enzymes capable of posttranslational modification (arginase and kinases), as well as important viruses (COVID-19, HPV).
• Imaging of Biophysical Barriers in Cancer, Spectral Imaging, and Micrometastases
  • Ultra-high-resolution imaging techniques (micro-CT, ultra-high-field MRI and optical tomography) permit the imaging of biophysical barriers in cancer (e.g. interstitial collagen and hyaluronic acid deposits), as well as the directional diffusion characteristics of stromal interfaces. This will permit the quantitative understanding of drug transport into tumors in preclinical models, followed by clinical translation. Spectral MRI imaging enables simultaneous voxel-by-voxel pharmacokinetics, as well as the observation of metabolic changes in cancer. By using contrast-marker free ultra-high field MRI techniques, micrometastases can be quantitatively imaged. Any successful treatment methods of solid tumors have to block and reverse the formation of micrometastases, which otherwise can grow to metastases and are responsible for the majority of mortalities from cancer.
• Advanced Drug Delivery and Drug Delivery Materials
  • My research has been concerned with various types of vesicles for drug delivery purposes (against cancer and infectious diseases, such as Mycobacterium tuberculosis and Methicillin-resistant Staphylococcus aureus) since 2004. Recently, we have discovered a new class of copper(I)-binding drugs with so-called NNSN-motif that feature nanomolar activities against solid pancreatic cancer and glioblastoma. We also have established rationally designed peptide nanosponges as versatile nanosystems for drug delivery to tumors and defensive cells. My group also has experience in synthesizing tailored magnetic and carbon nanomaterials derived from detonation-graphene.

The overall goal of our research is to develop novel nanotechnology for early detection of cancer and treatments. Nanobiosensors were developed for protease activity measurements that serve as cancer biomarkers for an early detection of solid tumor (pancreatic, lung, and triple negative breast cancer) by means of liquid biopsies (serum samples). Also, polymer based nanocarriers and peptide based nanosponges have been developed for genetic information and small molecules/drug delivery.

Dr. Dandawate's research interest involves understanding key signaling pathways in cancer cells and how targeting these pathways with natural or synthetic compounds as well as the repurposing of FDA-approved drugs will contribute to improved treatment for cancer patients. Many anticancer drugs have the problem of water solubility and metabolic instability and hence use of drug delivery systems especially cyclodextrin-based formulations to overcome these problems is one of his interests. Following are ongoing projects he is working on.

1. Studying the role of taste receptors in the colon and esophageal cancers.
2. Establishing the role of histone demethylase KDM3A in pancreatic cancer.

Our research focus has been on developing a molecular biology-based toolkit to support cancer research. We are utilizing cell-free methods to generate nucleic acids as RNA and/or proteins and combining them with nanocarrier delivery to improve cancer therapeutics and detection. We are developing unconventional methods to produce purified proteins with human post-translational modification that can be customized based on the downstream applications.

CRC remains the second most common cancer and second leading cause of cancer-related death in men and women combined. Lifestyle and behavior factors such as obesity, diabetes and cigarette smoking increase the risk of developing CRC, but the mechanism of influence on CRC biology is less clear. Research in the Davis lab centers on the hypothesis that understanding the effects of lifestyle and behavioral risk factors on CRC biology can be used to improve the efficacy of early detection and chemoprevention strategies and reduce the harms in those who are unlikely to benefit from such interventions. Studies in the Davis lab utilize 1) animal models of CRC development, 2) hospital-based patient datasets and 3) large longitudinal studies.

Role for Type 1 Interferon Signaling in Promoting Endocrine Resistance in Breast Cancer
Despite the benefits of endocrine therapies such as tamoxifen and aromatase inhibitors in treating estrogen receptor alpha (ERa)-positive breast cancer, many tumors eventually become resistant. Identifying the underlying cellular and molecular mechanisms responsible for endocrine resistance remains a critical and immediate need. Our laboratory is interested in identifying novel pathways of endocrine-resistance in breast cancer and using that knowledge to help develop alternative treatment options for patients with endocrine resistant and metastatic disease. We have identified a novel role for the interferon alpha (IFNa) signaling pathway in promoting aromatase inhibitor resistance in ER-positive breast cancer. Indeed, our lab has shown that Al-resistant breast cancer cells and resistant tumors secrete elevated levels of IFNa which upregulates JAK/STAT signaling to promote constitutive activation of IFNa-stimulated genes (ISGs) and drive cell survival. One ISG is IFITMI (interferon-induced transmembrane protein 1) which is overexpressed in AI-resistant cells and resistant tumors and its loss leads to cell death through activation of p21^Waf1. The long-term goal of this project is to understand the role of type 1 interferon signaling in endocrine resistance and the impact of the microenvironment on this process. Type 1 IFNs are cytokines that regulate antiviral responses through activation of the JAK-STAT signaling pathway, however, their impact on epithelial-stromal interactions in the tumor microenvironment and their potential contribution to the development of Al-resistance through crosstalk with the ERa signaling pathway are not known.

Molecular underpinnings of Triple Negative and Inflammatory Breast Cancer
Dr. Lewis-Wambi’s lab also studies triple negative breast cancer (TNBC) and inflammatory breast cancer (IBC) which are two aggressive and lethal subtypes of breast cancer that are difficult to diagnose and treat and disproportionately affect African American (AA) women compared to other ethnic groups. Her lab has identified a novel marker called interferon induced transmembrane protein 1 (IFITM1) that appears to be highly expressed in TNBC tumors and TNBC cell lines derived from AA patients but not expressed in TNBC tumors from Caucasian patients and its overexpression enhances the aggressive phenotype of TNBC cells in culture. Her research efforts are focused on characterizing the role of IFITM1, in the pathobiology and progression of TNBC in African American patients and assess whether targeting IFITM1 has therapeutic benefits in vivo and whether it can serve as a novel diagnostic marker of cancer progression and metastasis.

My current research focuses on enhancing the available preclinical imaging techniques while simultaneously developing new protocols and analysis strategies.

T-cells are vital immune cells which play a key role in fighting infections and cancer. Dysregulation of T-cells is a contributing factor in many inflammatory autoimmune diseases in humans, like multiple sclerosis, colitis and rheumatoid arthritis as well as in susceptibility to infections and cancers. Our research focuses on understanding the metabolic mechanisms governing the T cell mediated immune responses. We are looking into the role of stress-responsive antioxidant system in T cell development and effector functions. We use a multidisciplinary approach involving immunologic, biochemical and metabolic assays to identify and decipher the role of different signaling pathways, nutrients and other factors in deciding the fate of T cells and their ability to elicit an immune response against pathogens and tumors.

Dr. VanSaun's lab focuses on understanding the influence of adipose secreted cytokines (adipokines) on pancreatic cancer progression. The epidemic of obesity is a significant risk factor, associated with 40% of all cancers, including pancreatic cancer, which ranks as the third deadliest cancer with an approximate five-year survival rate of 9%. Obesity associated inflammation incites a yin/yang dysregulation of adipokines, whereby pro-tumorigenic adipokine (leptin, IL-6 and IL-1β) levels increase and anti-tumorigenic adipokine (adiponectin) levels decrease. This dysregulation results in enhanced activation of mitogenic pathways, such as KRAS, that drive cancer progression and promote the recruitment of innate inflammatory cells. We have spent the past eight years studying adipocyte-tumor crosstalk and understanding how secreted factors from the adipose tissue (adipokines) ultimately affect the tumor microenvironment. We have developed mouse and human in vitro PDAC-adipocyte co-culture models as well as in vivo genetically engineered mouse models of pancreatic cancer combined with high fat diet induced obesity to understand the impact of obesity on pancreatic cancer progression. We currently have multiple projects ongoing in the laboratory to understand: 1) role of adipose-tumor crosstalk in pancreatic cancer progression, 2) role of tyrosine phosphatases in regulation of MAPK signaling, 3) regulation of immune function in the tumor microenvironment, 4) metabolic alterations in response to phosphatase activity, 5) the potential use of adiponectin agonists as anti-cancer therapeutics.

Applying innovative proteomic and cellular technologies to the study of chromatin remodeling complexes in cancer.

Chromatin Remodeling Complexes and Interaction Networks in Cancer. Critical mutations in chromatin remodeling proteins are routinely found in cancer genomics studies and therapeutics that target chromatin remodeling complexes are of great interest for the treatment of cancer. For example, HDAC 1 and HDAC2 are enzymes whose inhibitors are under investigation in many ongoing clinical trials, and these proteins are members of several distinct protein complexes like the SIN3A and SIN3B protein complexes. SIN3A and SIN3B are paralogues that define distinct protein complexes that play key roles in chromatin remodeling. Mutations in SIN3A are considered potential cancer drivers in diseases like Uterine Corpus Endometrial Carcinoma. In addition, SIN3A and SIN3B have been shown to deferentially regulate breast cancer metastasis. Our laboratory is pursuing ongoing studies regarding the structure and function of HDAC1. HDAC2, SIN3A, and SIN3B protein complexes in normal and diseased states.

Integrated Structural Modeling of Protein Complexes. We seek to develop and integrate new and emerging technologies in pursuit of our studies of the structure and function of chromatin remodeling complexes. To do so, we have been adopting exciting new and powerful cross-linking mass spectrometry technologies . Integration of cross-linking mass spectrometry data with state-of-the-art computational approaches allows one to build structural models of complexes using integrative approaches. We have used these techniques to begin to build integrated structural models of chromatin remodeling complexes like the SIN3A complex and the Spindlin1:SPINDOC protein complex.

ProteoCellomic analysis of Protein Complexes and Protein Interaction Networks. We have a long-standing interest in the study of protein complexes and protein interaction networks and have developed technologies and approaches that seek to advance the field. To do so, we have adopted multifunctional tags like the HaloTag and SNAP-tag. These tags can be used for affinity purification of protein complexes in addition to the study of tagged proteins in live cells. We have developed a serial capture affinity purification (SCAP) approach using these tags where two distinct proteins are tagged with the HaloTag or SNAP-tag and specific and enriched protein complexes that can be isolated using a sequential purification approach. Live cell imaging is then used to investigate the quantitative nature of specific protein interactions. Next, using cross-linking mass spectrometry and computational approaches an integrated structural model of the enriched protein complex can be generated.

My academic role at KUMC is focused on product development-focused translational science. I direct the Institute for Advancing Medical Innovation (IAMI) at KUMC. IAMI translates peer review-funded basic research into medical innovations, and using an industry approach, executes product development-focused translational research to de-risk the technologies with the intent of partnering those with promise. To date, IAMI has invested over $11M in 68 projects, 18 of which have resulted in royalty-bearing licenses. IAMI’s therapeutic areas of focus are cancer and rare diseases. Therapeutics, diagnostics, and medical devices are the priority technology areas, while IAMI is opportunistic when it comes to investing in advancing medical devices. Multi-disciplinary, multi-organizational project teams are formed with IAMI leadership. Empowered project teams are guided to develop milestone-based product development-focused translational research project plans.