Next-Generation Targeted Therapy in Mantle Cell Lymphoma and Transformed Follicular Lymphoma

Steven Park

MD

Atrium Health Foundation

Project Term: July 1, 2024 - June 30, 2027

Targeted therapy has revolutionized cancer treatment and become the dominant therapeutic modality in the modern era. However, we recognize that small molecule drugs suffer from drug resistance and treatment-related toxicity, leading to most patients discontinuing treatment while on targeted therapy. To overcome these shortcomings, we have developed a next-generation targeted strategy by delivering potent dual/triple inhibitors by pretargeted nanoparticles (NPs) to minimize toxicity and overcome drug resistance in lymphoma therapy.

We understand that CDK4/6 inhibition in mantle cell lymphoma (MCL) results in rapid drug resistance by the cancer cell, and there is an unmet medical need to develop more effective targeted agents that will augment the activity of CDK4/6 inhibition in MCL. Our central hypothesis is that combined triple inhibition of CDK4/6, PI3K, and BRD4 pathways with one small molecule will be more efficacious and less toxic than a combination of three separate drugs. To support our hypothesis, we have designed and synthesized a potent first-in-class triple small molecule inhibitor, LCI132, against CDK4/6, PI3K, and BRD4. In addition, our group has developed MS177, a potent first-in-class dual proteolysis targeting chimera (PROTAC), for concurrent breakdown of EZH2 and MYC proteins that has shown promising results in transformed follicular lymphoma (tFL) cells.

On-target (target-specific) toxicity remains a concern for small molecule drugs, including dual and triple inhibitors. For example, more than 60% of lymphoma patients treated with idelalisib, a PI3K inhibitor, suffer serious side effects, such as colitis and pneumonitis, while being on the targeted therapy. Therefore, we have developed a high precision drug delivery platform using pretargeted nanoparticles (NPs) to minimize toxicity arising from small molecule drugs. As a proof of concept, our group successfully developed a pretargeted NP platform to deliver BEZ235, a dual PI3K/mTOR inhibitor, which increased the therapeutic index by greater than 10-fold compared to the current standard drug formulation. We are confident that pretargeted NP delivery of LCI132 and MS177 will enhance efficacy and safety of targeted therapy, which is essential in advancing cancer therapy.

Our research has the potential to significantly improve the effectiveness of small molecule drugs while reducing associated toxicity. We hope that this approach will ultimately increase the survival rates of patients suffering from MCL and tFL that are resistant to conventional chemotherapy and targeted therapy. Ultimately, we hope to provide new tools to other investigators in their efforts to improve efficacy and toxicity of their small molecule drugs. This innovative system has the potential to revolutionize the field of targeted therapeutics and improve treatment outcomes for many types of cancer.