Cancer Therapeutics

Investigators

EphA2 receptor tyrosine kinase as a target for cancer therapy.

Bingcheng Wang, PhD

EphA2 belongs to the Eph family of receptor tyrosine kinases. Extensive studies have implicated EphA2 overexpression in the malignant progression of many solid tumor types. Converging evidence shows that the EphA2 receptor is an attractive target for cancer. The Wang lab recently uncovered dual roles of EphA2 in tumor etiology and malignant progression. When engaged with ligands (ephrin-As), EphA2 is a tumor suppressor and inhibits both ERK and Akt activities in GBM cells.

However, without ligands, EphA2 is phosphorylated by AGC kinases including Akt and p90-RSK on serine 897. S897 phosphorylation converts EphA2 from a tumor suppressor into an oncogenic protein that promotes tumor cell growth and migration in vitro and invasion and metastasis in vivo. Moreover, pS897-EphA2 regulates the cancer cell stem properties. In contrast, upon ligand stimulation, pS897 is dephosphorylated, and the activated EphA2 induces tumor cells differentiation and inhibits tumor development. Based on this series of observations, it was proposed that ligand-mimicking small molecule agonists of EphA2 can be novel therapeutic agents for cancer.

Such agonists are expected to i) restore the intrinsic tumor suppressor functions of EphA2, ii) disrupt the pro-oncogenic Akt/RSK-EphA2 signaling axis, and iii) induce differentiation of cancer cells. Using structure-guided virtual screening and cell-based assays, we reported that doxazosin (DZ), an 1-adrenoceptor antagonist still in clinical use for hypertension, is a bona fide EphA2 agonist. DZ inhibits ERK and Akt and suppresses tumor cell dissemination in an EphA2-dependent manner. Much more potent derivatives of DZ have been characterized through medicinal chemistry, including BW27, which suppressed tumor development in preclinical models. A major goal of the Wang lab is to translate these basic and preclinical discoveries into novel cancer therapeutic agents.

Selected Publications

Li Y, Orahoske CM, Geldenhuys WJ, Bhattarai A, Sabbagh A, Bobba V, Salem FM, Zhang W, Shukla GC, Lathia JD, Wang B*, Su B*. (2021). Small-Molecule HSP27 Inhibitor Abolishes Androgen Receptors in Glioblastoma. J Med Chem. 64:1570-1583. PMID: 33523674. doi: 10.1021/acs.jmedchem.0c01537. *Co-corresponding authors.

Orahoske CM, Li Y, Petty A, Salem FM, Hanna J, Zhang W, Su B*, and Wang B*. Dimeric small molecule agonists of EphA2 receptor inhibit glioblastoma cell growth. 2020, Bioorg Med Chem. 15:115656 PMID: 32828423. *Co-corresponding authors.

Petty A, Idippily N, Bobba V, Geldenhuys WJ, Zhong B, Su B, Wang B. (2018) Design and synthesis of small molecule agonists of EphA2 receptor. Eur J Med Chem. 143:1261-1276. doi: 10.1016/j.ejmech.2017.10.026.

Identifying YB1 as a Biomarker/Therapeutic Target of Triple-negative Breast Cancer

Khalid Sossey-Alaoui, PhD

Amongst individual breast cancer subtypes, those classified as triple-negative breast cancers (TNBCs) are especially lethal due to their highly metastatic behavior and propensity to rapidly recur. As a group, TNBCs lack expression of hormone receptors (ER-α and PR) and ErbB2/HER2. These molecular deficits have prevented the development of FDA-approved targeted drug therapies to treat this breast cancer subtype. Likewise, recurrent TNBCs quickly acquire resistance to standard-of-care chemotherapeutic agents through mechanisms that remain incompletely understood.

We discovered YB1, a multifunctional gene, as a potential biological driver of TNBC tumor progression, metastasis, therapy resistance, and immune evasion. Our preliminary and published data found YB1 expression levels, its nuclear localization and phosphorylation to be significantly higher in basal (TNBC) breast cancer subtype compared to their luminal and Her2 counterparts. We also found increased YB1 activity to stimulate the cancer stem cell (CSC) phenotype, which promotes chemoresistance and TNBC metastasis; to activate cell cycle signaling; and to induce immune evasion of TNBC tumors. Our current research is focusing on the therapeutic targeting of YB1, in combination with standard of care chemotherapies or with immune checkpoint inhibitors as potential therapeutic approaches for the treatment of TNBC tumors.

We also developing a biomarker strategy, where phosphorylation and/or nuclear localization YB1 can be used as a biomarker to predict response to therapy in women with TNBC. In another research project, we established WAVE3 as a major driver during the process of acquisition of the invasive and metastatic phenotypes in TNBCs. We are currently developing a nanoparticles platform to specifically deliver WAVE3 inhibitors to TNBC tumors to restore/enhance the sensitivity of TNBCs to chemotherapy as a means to alleviate TNBC progression and metastasis. Our innovative multidisciplinary and medically relevant approach will certainly contribute greatly to our understanding of TNBC biology, and will identify new YB1- and WAVE3-based therapeutic options for this devastating cancer. Importantly, our findings will significantly impact the diagnosis, prognosis, and eventual treatment of TNBCs, thereby improving the clinical outcome for patients bearing this deadly disease.

Selected Publications

Rana PS; Wang W; Alkrekshi A; Markovic V; Khiyami A; Chan R; Perzynski A; Joseph N and Sossey-Alaoui K. YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer. Cancers (Basel). 2021 Dec 14;13(24):6262. doi: 10.3390/cancers13246262.

Alkrekshi A; Wang W; Rana PS; Markovic V and Sossey-Alaoui K. A comprehensive review of the functions of YB-1 in cancer stemness, metastasis, and drug resistance. Cell Signal. 2021 Jul 3;85:110073.

Complete List of Publications

https://pubmed.ncbi.nlm.nih.gov/?term=%28sossey-alaoui%29+NOT+%28Geffard%29&sort=pubdate