Prostate cancer (PCa) is a leading cause of death among American men. Nearly all of these deaths are due to the
evolution of therapy resistance and metastatic spread. As such, there is an urgent, unmet need to develop new agents
to treat therapy-resistant, metastatic PCa. The long noncoding RNA (lncRNA) Second Chromosome Locus Associated
with Prostate 1 (SChLAP1) has been identified as the top RNA associated with prostate cancer-specific mortality and
metastasis from multiple datasets with long-term follow up. Knockdown/overexpression of SChLAP1 is associated
with changes to pro-metastatic phenotypes, such as invasion and colony formation. Targeting this critical cellular
regulator has been elusive, however, and its mechanism of action in promoting PCa therapy resistance and metastasis
has not been fully elucidated. For example, an interaction between SChLAP1 and the SWI/SNF complex has been
implicated in PCa progression in some studies, but not in others. This gap in knowledge regarding the molecular
function of SChLAP1 prevents effective therapeutic targeting of SChLAP1. Recent work by our team and others has
revealed a complex RNA architecture within SChLAP1 as well as protein binding regions localized to highly structured
and primate-conserved regions of the transcript. This compelling evidence for functional RNA structures, combined
with the availability of SChLAP1 as a biomarker in urine and blood, renders targeting of lncRNA SChLAP1 a promising
precision medicine-based treatment approach for men with aggressive PCa.
The overall objectives of the proposed work are to: 1) identify and characterize protein interactors and
chromatin-binding sites critical to SChLAP1 oncogenic activity and 2) validate drug-like ligands identified in recent
screens as tool molecules for targeting structured regions of SChLAP1, including inhibition of these interactions and
SChLAP1-driven phenotypes. The central hypothesis is that the mechanism of SChLAP1 involves interactions with
both protein and chromatin, and that targeting these interactions will inhibit SChLAP1-driven phenotypes and reveal
novel therapeutic avenues to treat metastatic, treatment-resistant PCa. In Aim 1, unbiased sequencing and mass
spectrometry-based approaches will identify chromatin regions and proteins bound by SChLAP1 in cells, and these
interactions will be interrogated in an array of phenotypic assays to evaluate their role in proliferation, cancer cell
survival, migration/invasion, and resistance to standard-of-care hormone therapy. In Aim 2, ligands of conserved
SChLAP1 substructures will be validated in phenotypic assays, and their effects on molecular interactions will be
interrogated. Expected outcomes of this work will be as follows: 1) comprehensive biological insight into targetable
intermolecular interactions for SChLAP1 and 2) identification of small molecules that inhibit SChLAP1:protein
interactions and subsequent phenotypes in PCa. This work will set the stage for a future R01 proposal focused on in
vivo validation studies for small molecules targeting SChLAP1 and the development of an exosome-based liquid
biopsy for SChLAP1, with the ultimate goal of yielding a precision medicine-based strategy for aggressive and
treatment-resistant PCa while also helping to establish lncRNA targeting as a therapeutic paradigm in oncology.