In order to overcome BTK inhibitor resistance, the Wang Laboratory employs a multipronged approach in concert with the B-cell Lymphoma Moon Shot®.
We have created a high throughput screening system to test the therapeutic efficacy of novel inhibitors in MCL and other B-cell lymphomas. Using this system of screening novel agents in cell lines and patient primary cells, we have identified compounds that can overcome both ibrutinib and venetoclax resistance in B-cell lymphoma (Huang & Wang et al., Blood Cancer Journal, 2018; Pham & Wang et al., Clinical Cancer Research, 2018).
Genomics and Profiling Approach
We have performed whole exome sequencing (WES), RNA sequencing (RNA-seq), proteomics analysis, and metabolomics analysis on MCL cell lines, patient clinical specimens, and patient-derived xenograft (PDX) mouse model tissue.
MCL PDX Mouse Model
We were the first laboratory to develop an MCL PDX mouse model (Wang et al., Clinical Cancer Research, 2008), and this model has become indispensable to our laboratory (Zhang et al., Clinical Cancer Research, 2017). We utilize this model as a drug discovery tool, which we have employed in concert with in vitro drug efficacy screening and molecular profiling, to identify novel therapies for ibrutinib-resistant MCL. This research resulted in an R21 award: “Overcoming Primary Ibrutinib Resistance in Mantle Cell Lymphoma Using Patient-Derived Models and Molecular Profiling.”
We also utilize this PDX mouse model to understand the mechanistic basis of therapeutic resistance and cancer progression, as well as to develop personalized therapies for B-cell lymphoma. To personalize therapy to treat MCL and other B-cell lymphomas, we have proposed to guide therapy based on each individual patient’s PDX mouse model married with molecular profiling and in vitro drug efficacy screening. This concept has resulted in an IRB-approved protocol that is awaiting activation and numerous funding awards.
In addition to personalizing therapy with the PDX mouse model, we have also proposed an innovative trial design to identify effective patient-specific therapies for relapsed/refractory MCL patients by analyzing the patient somatic/tumor mutation profile and conducting in vitro drug efficacy assays, which has also been a primary component of the B-cell Lymphoma Moon Shot.
Lastly, we are developing a unique and sensitive assay to detect minimal residual disease (MRD) in patients via mutational analysis of circulating tumor (ct) DNA. Currently, we have assessed patient MRD status via liquid biopsy to detect ctDNA using two methods: hybridization capture, and a PCR-enrichment assay using an MCL-specific circulating tumor DNA (ctDNA) target gene panel. We are continuing to assess follow-up plasma samples to determine if early molecular relapse can be detected, and we believe a MCL-specific PCR-enrichment assay, in collaboration with Archer DX, has potential to be patented.