Dean, School of Pharmacy; Professor, Department of Pharmaceutics
Accepting Students to Lab: Yes
- PhD in Pharmaceutical Sciences, University of Nebraska Medical Center
- Master of Pharmacy (Pharmaceutics), Banaras Hindu University
- Bachelor of Pharmacy, Tamil Nadu Dr. M.G.R. Medical University
- Targeting the premetastatic niche
- Novel TLR7/8 agonists as anticancer vaccine adjuvants
- Antibody-drug conjugates
Drug delivery systems that are in the ~100 nm size range have been of considerable interest in the field of anti-cancer drug delivery. However, the therapeutic benefit of such systems (for example, liposomal doxorubicin – Doxil® and albumin-bound paclitaxel – Abraxane®) have been realized in only a subset of tumor types, and even in these tumors, the survival benefits have been modest. A detailed understanding of the biological fate of delivery systems and, more importantly, in the microenvironment of the target tissue is necessary to further improve treatment efficacy. For several years, our research was focused on investigating the mechanisms of anticancer drug delivery, with emphasis on understanding how various biological factors influence the effectiveness of various delivery approaches. The ultimate goal is to use the knowledge derived from these studies to devise advanced delivery platforms that can be effectively translated to the clinic. More recently, our focus has broadened to include antibody-drug conjugates as a platform technology for targeting cancer cells. Similarly, we now emphasize eliciting body’s own immunological defenses to fighting cancer. Finally, we have begun to understand how primary tumors start programming vascular organs such as lungs and liver to facilitate metastasis. We are now developing strategies to interfere with this premetastatic niche formation. Specific ongoing projects include:
Targeting the premetastatic niche (PMN)
Metastatic disease continues to be the major cause of mortality in patients with most solid tumors. Significant advances have been made in understanding the changes in tumor cells and the tumor microenvironment that eventually result in secondary lesions. Accordingly, much of the current drug discovery efforts are focused on targets in tumor cells or the primary tumor microenvironment. However, fewer attempts have been made to target the changes that occur in secondary organs before and during metastatic colonization. Recent studies show that primary tumors actively program organs such as the lungs and liver to create the PMN. Our group has been working to understand how changes that occur in the PMN can be targeted to prevent metastatic growth. In patients with metastatic tumors, myeloid-derived suppressor cells (MDSCs) are significantly increased in circulation. Similarly, in mouse models, MDSCs increase in circulation and actively home to premetastatic sites. MDSCs promote metastasis by activating dormant tumor cells via pro-inflammatory S100A8/A9 proteins. The goal of this research is to investigate various small molecule inhibitors and novel biologics to interfere with trafficking of MDSCs to the premetastatic niche and signaling via the S100A8/A9 proteins.
Novel TLR7/8 agonists as anticancer vaccine adjuvants
Agonists of toll like receptors (TLRs) are promising anticancer vaccine adjuvants because of their ability to induce proinflammatory cytokines necessary to generate a robust immune response. However, currently available TLR agonists suffer from several limitations including self-regulatory immunosuppression and unfavorable local pharmacokinetics resulting in poor availability within dendritic cells. Further, current TLR agonist-based anticancer vaccines generate a robust cytotoxic CD8 T cell response but not CD4 Th1 helper T cell response, which is critical for inducing effective, long-term antitumor immunity. We are addressing these important challenges through a synergistic combination of drug discovery and drug delivery efforts. Our team has developed a suite of highly substituted imidazoquinolines, which activate TLR7 and/or 8 and induce significantly higher levels of cytokines compared to imiquimod, an FDA approved TLR7 agonist. Our studies show the balance between pro-inflammatory and immunosuppressive cytokines can be tuned through structural modifications. Encapsulation of these novel agonists in acidic pH responsive nanoparticles (NPs) resulted in robust activation of CD4 and CD8 T cells as well as natural killer (NK) cells, leading to a stronger anticancer immune response than free agonist or that encapsulated in non-pH responsive NPs. Importantly, intradermal delivery of NP vaccine using a hollow microneedle platform led to an enhanced Th1 immune response, which is essential for effective induction of long-term antitumor immunity. Our current studies are focused on further optimizing the new agonists for efficient encapsulation in pH responsive NPs, tune the NP properties for improved targeting of dendritic cells following delivery via hollow microneedles, and investigate potentiation of NK cell-mediated antibody-mediated cellular cytotoxicity.
Antibody-drug conjugates targeting HSPG2 (perlecan)
Bladder cancer (BC) is the most common cancer of the urinary tract. Patients with muscle-invasive disease have a 5-year survival rate less than 50%. Treatment methods for advanced BC have not changed for more than 20 years. Our long-term goal is to develop effective therapeutic strategies against metastatic BC. We have recently identified the overexpression of a cell surface protein called perlecan (HSPG2) on BC cells. Gene expression analysis shows that patients with high HSPG2 expression have a significantly lower survival rate compared to those with low HPSG2 expression, pointing to clinical significance of this novel biomarker. In addition, we have developed a monoclonal antibody (AM6) targeting HSPG2. Conjugation of the cytotoxic drug MMAE to AM6 enables effective targeting of BC cells and results in potent tumor cell kill. The objective of this research is to further develop and evaluate the efficacy of AM6-based antibody-drug conjugate (ADC) in cell culture and mouse models of BC. Our studies are also focused on understanding the structural features of AM6 that could impact its therapeutic efficacy. Further, since HSPG2 is overexpressed in many different solid tumors including breast and ovarian cancer as well as in melanoma, we expect that HSPG2-targeted ADC could be of significant therapeutic benefit.