Park laboratory is interested in understanding the mechanism of drug resistance and developing novel targeted and immunotherapeutic strategies to treat cancer.
Cancer Cell Signaling: We have investigated the mechanism of resistance to BCL2 inhibition and the effect of aurora kinase (AURK) inhibition in BCL2-rearranged lymphomas, such as follicular lymphoma and double-hit lymphoma. Our data demonstrate that BCL2-rearranged lymphomas harbor intrinsic resistance to BCL2 inhibition via rapid and profound downregulation of the TP53 axis. This may explain the relative lack of clinical activity associated with venetoclax, a Bcl-2 inhibitor, in BCL2-rearranged lymphomas. Inhibition of AURK effectively restores the TP53/p21/BAX pro-apoptotic axis in resistant lymphoma cells, making BCL2-rearranged lymphomas exquisitely sensitive to the combined inhibition of BCL2 and AURK. Furthermore, the combination of venetoclax and MLN-8237, an AURK inhibitor, demonstrates excellent efficacy and favorable toxicity profiles in BCL2-rearranged lymphoma animal models, hence laying the groundwork for further evaluation of this combination in clinical settings. https://www.sciencedirect.com/science/article/pii/S0006497121026720
NextGen Targeted Therapy Platform: Our group has engineered a high precision drug delivery platform using pretargeted NPs. This novel NP system employs bi-orthogonal “click” chemistry to deliver small molecules directly to the tumor to minimize off-target as well as on-target toxicities arising from multi-target inhibition. As a proof of concept, our group has successfully developed a pretargeted NP platform to deliver BEZ235, a dual PI3K/mTOR small molecule inhibitor, and the pretargeted NP platform led to an 8-fold increase in tumor uptake and a 10-fold increase in the therapeutic index (Effective Dose to Toxic Dose Ratio) compared to the conventional delivery of the free small molecule drug, in lymphoma animal models. We aim to further investigate this novel targeting platform by loading potent small molecule drugs in pretargeted NPs for treatment of lymphoma. https://pubmed.ncbi.nlm.nih.gov/32270047/
Cellular immunotherapy using targeted NK cells: We have explored novel strategies to enhance cellular immunotherapy. Our group has developed a NP-based trispecific NK cell engager platform that can target epidermal growth factor receptor (EGFR)–overexpressing tumors and promote the recruitment and activation of NK cells to eradicate the target cancer cells. We have demonstrated that effective NK cell activation can be achieved by coactivation of CD16 and 4-1BB stimulatory molecules on NK cells with nanoengagers, and the nanoengagers are more effective than free antibodies. Trispecific nanoengagers can augment both NK-activating agents and chemotherapy as highly effective anticancer agents, providing robust chemoimmunotherapy.
Steven Park, MD
|Larry Druhan, PhD||Supriya Chakraborty, PhD|
|Sera Seegers, MS
||Margaret Templeton, BS