Research

Ongoing projects:

Subverting lineage plasticity to enhance therapeutic efficacy

We have made discoveries in both bladder cancer and cholangiocarcinoma that identify lineage plasticity — the ability of cancer cells to switch cell identities such as between and basal and luminal lineages — as important regulators of drug resistance and tumor aggressiveness. We are working to systematically uncover the main regulators of lineage plasticity and determine how they can be therapeutically targeted, either directly or indirectly.

Overcoming drug resistance

We have two major efforts in bladder and colon cancer to overcome drug resistance. In bladder cancer, we have conducted a CRISPR screen to identify new drugs that potently enhance FGFR inhibitors, which include modulators of lineage plasticity. In colon cancer, we have identified a new non-genomic mechanism of resistance to KRAS-G12C inhibitors and are currently seeking approaches to overcome the resistance and to understand how it evolves.

Understanding how chromatin modifiers works in cholangiocarcinoma and melanoma

How ARID1A, ARID2, PBRM1 and BAP1, frequently mutated tumor suppressor genes, function is of great interest, as it could lead to improved therapies targeting their vulnerabilities. We are generating new models and will aim to catalog and understand how these genes are similar and different from each other.

Exploring the role of S6K1 in melanoma drug resistance

S6K1 is the primary kinase that phosphorylates S6, a ribosomal gene at the center of many processes related to cancer growth. Many studies have identified S6K1 as a potential target to reverse kinase inhibitor resistance. We have uncovered novel context-dependent roles for S6K1 and its paralog S6K2 in BRAF inhibitor resistance in BRAF-mutant melanoma and are systematically dissecting their best use as drug targets for specific patients.

Establishing new models and cell lines for cholangiocarcinoma

Very few such cell lines exist in the entire world, so we're attempting to create a cell line bank at MD Anderson. We are also creating a new cholangiocarcinoma model using mouse modeling.