Showing papers by "Gary K. Scott published in 2015"

Inhibition of proline catabolism for the treatment of cancer and other therapeutic applications

Abstract: In various embodiments a cancer treatment method is provided based on inhibition of proline catabolism. When combined with p53 restoration therapy and/or inhibition of glutaminase, the inhibition of proline catabolism results in a “synthetic lethal” and synergistic anticancer response. Novel suicide inhibitors that induce the degradation of proline dehydrogenase (PRODH) are also provided. Also provided is a method of assaying PRODH to identify responders/non-responders to inhibition of proline catabolism and/or glutaminase.

FOXM1 cistrome predicts breast cancer metastatic outcome better than FOXM1 expression levels or tumor proliferation index

Abstract: FOXM1 is a key transcription factor regulating cell cycle progression, DNA damage response, and a host of other hallmark cancer features, but the role of the FOXM1 cistrome in driving estrogen receptor-positive (ER+) versus estrogen receptor-negative (ER-) breast cancer clinical outcomes remains undefined. Chromatin immunoprecipitation sequencing (ChIP-Seq) coupled with RNA sequencing (RNA-Seq) analyses was used to identify FOXM1 target genes in breast cancer cells (MCF-7) where FOXM1 expression was either induced by cell proliferation or repressed by p53 upregulation. The prognostic performance of these FOXM1 target genes was assessed relative to FOXM transcript levels and a 61-gene proliferation score (PS) for their ability to dichotomize a pooled cohort of 683 adjuvant chemotherapy-naive, node-negative breast cancer cases (447 ER+, 236 ER-). Differences in distant metastasis-free survival (DMFS) between the dichotomized expression groups were determined by Cox proportional hazard modeling. Proliferation-associated FOXM1 upregulation induced a set of 145 differentially bound and expressed genes (direct targets), and these demonstrated minimal overlap with differentially bound and expressed genes following FOXM1 repression by p53 upregulation. This proliferation-associated FOXM1 cistrome was not only better at significantly predicting metastatic outcome of ER+ breast cancers (HR: 2.8 (2.0-3.8), p = 8.13E-10), but was the only parameter trending toward significance in predicting ER- metastatic outcome (HR: 1.6 (0.9-2.9), p = 0.087). Our findings demonstrate that FOXM1 target genes are highly dependent on the cellular context in which FOXM1 expression is modulated, and a newly identified proliferation-associated FOXM1 cistromic signature best predicts breast cancer metastatic outcome.

Impairment of the large ribosomal subunit protein rpl24 by depletion or acetylation

Abstract: Provided herein are compositions of histone deacetylase (HDAC) inhibitors for the treatment of cancers overexpressing the large ribosomal subunit protein 24 (RPL24) in a subject in need thereof. Provided herein are methods for treating RPL24-overexpressing cancers in a subject in need thereof, comprising administering to the subject an effective amount of an HDAC inhibitor. Also provided herein are methods for inhibiting the viability of an RPL24-overexpressing cancer cell with an HDAC inhibitor. Also provided herein are methods for assessing the efficacy of an HDAC inhibitor against a cancer.

Abstract 5402: A new anticancer strategy based on inhibiting mitochondrial proline dehydrogenase (PRODH) and exploiting synthetic lethal interactions with p53 restoration and/or glutaminase (GLS1) inhibition

Abstract: From prokaryotes to the highest eukaryotes, proline is catabolized by a unique and structurally conserved flavoprotein, proline dehydrogenase (PRODH). In eukaryotes PRODH associates with the inner mitochondrial membrane and catalyzes the first and rate limiting catabolic step, transferring two electrons to the electron transport chain where they can produce ATP and/or reactive oxygen species (ROS). Following recognition that PRODH is one of the most strongly upregulated genes by the tumor suppressing protein, p53, its capacity to generate reactive oxygen species (ROS) and induce apoptosis initially qualified it as a tumor suppressing response, mediating the effects of p53 upregulation). However, we have definitively shown that while PRODH can induce mitochondrial ROS production it does so almost exclusively at other mitochondrial sites (e.g. complex I) via its anaplerotic glutamate production and not directly by itself. Furthermore, our recent studies indicate that PRODH critically supports breast cancer cell growth and survival by consuming proline for anaplerotic glutamate production, bypassing glutaminase (GLS1) to fuel oxidative phosphorylation and sustain ATP levels. We now show that PRODH knockdown, as well as its enzymatic inhibition by proline competitive inhibitors like L-tetrahydro-2-furoic acid (L-THFA) or (S)-5-oxo-2-tetrahydrofurancarboxylic acid (5-oxo), induce breast cancer cell apoptosis (cleaved PARP)and reduce viable cell growth within 48 h. Given that PRODH can provide an alternate source of mitochondrial glutamate for glutamine addicted and GLS1-dependent cancer cells, we evaluated the expression microarray profiles of 51 different human breast cancer lines and found a significant breast cancer subtype association with PRODH expression (luminal and HER2+ > basal-like), and also a strong inverse correlation between PRODH and GLS1 expression, suggesting that one or the other of these mitochondrial pathways is needed to feed breast cancer9s anaplerotic addiction to glutamate. Consistent with our hypothesis of synthetic lethal interactions between PRODH, p53wt upregulation and glutamine addiction, we combined PRODH knockdown or enzymatic inhibition with either a p53wt restoring drug (e.g. MI-63, nutlin-3a) or a clinical glutaminase (GLS1) inhibitor (CB-839, Calithera) and observed synergistic induction of apoptosis and growth inhibition against malignant (e.g. MCF7, ZR-75-1, DU4475) but not normal (MCF10A) breast epithelial cells. Using an in vitro mitochondrial PRODH bioassay and a computationally based structural model of human PRODH9s catalytic site, we are now designing new competitive and mechanism-based irreversible PRODH inhibitors capable of exploiting these synthetic lethal interactions to develop more effective and less toxic cancer therapy. Citation Format: Gary K. Scott, Justine Rutter, Katya Frazier, Daniel Rothschild, Christina Yau, Christopher Benz. A new anticancer strategy based on inhibiting mitochondrial proline dehydrogenase (PRODH) and exploiting synthetic lethal interactions with p53 restoration and/or glutaminase (GLS1) inhibition. [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 5402. doi:10.1158/1538-7445.AM2015-5402