Leisa Johnson

An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy

Replication-selective oncolytic viruses constitute a rapidly evolving and new treatment platform for cancer. Gene-deleted viruses have been engineered for tumor selectivity, but these gene deletions also reduce the anti-cancer potency of the viruses. We have identified an E1A mutant adenovirus, dl922-947, that replicates in and lyses a broad range of cancer cells with abnormalities in cell-cycle checkpoints. This mutant demonstrated reduced S-phase induction and replication in non-proliferating normal cells, and superior in vivo potency relative to other gene-deleted adenoviruses. In some cancers, its potency was superior to even wild-type adenovirus. Intravenous administration reduced the incidence of metastases in a breast tumor xenograft model. dl922-947 holds promise as a potent, replication-selective virus for the local and systemic treatment of cancer.

Selectively replicating adenoviruses targeting deregulated E2F activity are potent, systemic antitumor agents

We have engineered a human adenovirus, ONYX-411, that selectively replicates in human tumor cells, but not normal cells, depending upon the status of their retinoblastoma tumor suppressor protein (pRB) pathway. Early and late viral gene expression as well as DNA replication were significantly reduced in a functional pRB-pathway-dependent manner, resulting in a restricted replication profile similar to that of nonreplicating adenoviruses in normal cells both in vitro and in vivo. In contrast, the viral life cycle and tumor cell killing activity of ONYX-411 was comparable to that of wild-type adenovirus following infection of human tumor cells in vitro as well as after systemic administration in tumor-bearing animals.

Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes

The high failure rate of late-stage human clinical trials, particularly in oncology, predicates the need for improved translation of preclinical data from mouse tumor models into clinical predictions. Genetically engineered mouse models (GEMM) may fulfill this need, because they mimic spontaneous and autochthonous disease progression. Using oncogenic Kras-driven GEMMs of lung and pancreatic adenocarcinoma, we recently showed that these models can closely phenocopy human therapeutic responses to standard-of-care treatment regimens. Here we review the successful preclinical application of such GEMMs, as well as the potential for discovering predictive biomarkers and gaining mechanistic insights into clinical outcomes and drug resistance in human cancers.

Abstract 2259: Requirement for BUB1B in tumor progression of lung adenocarcinoma

Lung adenocarcinoma is often discovered as metastatic disease with very poor prognosis. However, much remains unknown about the mechanisms of lung adenocarcinoma tumor progression. In this study we showed that knockdown of BUB1B, a critical mitotic checkpoint protein, significantly inhibited anchorage-independent growth of lung adenocarcinoma cell lines. In allograft and tail vein mouse model studies, BUB1B suppression inhibited primary tumor growth and reduced metastasis to the lung and lymph nodes, resulting in prolonged survival in both tumor prevention and tumor intervention settings. Mechanistic studies revealed that BUB1B knockdown sensitized cells to anoikis. The N-terminal region of BUB1B was required for its functions in both anchorage-independent growth and anoikis resistance, whereas the kinase domain was less critical. Overexpression of BUB1B is associated with disease progression and poor survival in human lung adenocarcinoma patients. Collectively, these data reveal a novel function for BUB1B in mediating anchorage-independent survival and growth, thereby facilitating lung adenocarcinoma dissemination during metastasis. Thus, targeting BUB1B could provide potential therapeutic benefit in suppressing metastasis and prolonging survival in lung adenocarcinoma patients. Citation Format: Honglin Chen, James Lee, Noelyn M. Kljavin, Benjamin Haley, Anneleen Daemen, Yuxin Liang, Leisa Johnson. Requirement for BUB1B in tumor progression of lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2259. doi:10.1158/1538-7445.AM2015-2259