Chromosomal translocations, where a segment from one chromosome is joined to a heterologous chromosome, can result in fetal developmental abnormalities or a myriad of malignancies. For a chromosomal translocation to occur there must be: 1) simultaneous double strand breaks (DSBs) on heterologous chromosomes, and 2) re-ligation of the DSBs to heterologous and not homologous chromosomal free ends. Should the cell survive a translocation, it is at great risk for abnormal differentiation during fetal development, or for neoplastic transformation.

Replication fork stalling and collapse is a major source of genomic instability and subsequent neoplasia. Such stressed forks can be conservatively repaired and restarted using homologous recombination (HR) repair, initiated by generating an endogenous nick at the fork junction. While there are candidate nucleases for generating this DSB, most mammalian stressed forks can be restarted without these nucleases, and the origin of this nick remains undefined.

Human Papillomavirus (HPV) infections and associated diseases have been a chronic and growing health problem for the worlds population. HPV is now recognized as the carcinogen of almost all invasive cervical cancers and a major cause of other human malignancies including oropharyngeal and anogenital cancers totaling ~ 600,000 cases worldwide annually. Economically, HPV imparts a tremendous financial burden on the world health systems in terms of expenditure for HPV prevention, periodic surveillance and cancer treatments.

The proposed research direction is the manufacture and characterization of implantable, biodegradable polymer structures with engineered release profiles of drug payloads. These structures can be 3D printed in-house with complex geometries and composite structures, which we hypothesize will dissolve such that selective timing or staged release of one or more compounds is possible. While typically such payloads would be therapeutic in action, this platform technology is drug agnostic and can be used for image enhancement or theranostic applications as well.

This collaborative research project will further evaluate whether intrinsic alterations in these signaling pathways are biomarkers of drug response and. reciprocally. follow up on data indicating that the taccas can also alter the functional consequences of these signaling pathways. These studies are significant in that they will lead. in the future.