Publications by authors named "Salma Kaochar"

13 Publications

  • Page 1 of 1

Androgen receptor signaling inhibitors: post-chemotherapy, pre-chemotherapy and now in castration-sensitive prostate cancer.

Endocr Relat Cancer 2021 Jul 15;28(8):T19-T38. Epub 2021 Jul 15.

Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past eight decades. However, it quickly became evident that androgen deprivation therapy (ADT) via surgical or medical castration accomplishes inadequate inhibition of the androgen receptor (AR) axis, with clinical resistance inevitably emerging due to adrenal and intratumoral sources of androgens and other mechanisms. Early efforts to augment ADT by adding adrenal-targeting agents (aminoglutethimide, ketoconazole) or AR antagonists (flutamide, bicalutamide, nilutamide, cyproterone) failed to achieve overall survival (OS) benefits, although they did exhibit some evidence of limited clinical activity. More recently, four new androgen receptor signaling inhibitors (ARSIs) successfully entered clinical practice. Specifically, the CYP17 inhibitor abiraterone acetate and the second generation AR antagonists (enzalutamide, apalutamide and darolutamide) achieved OS benefits for PC patients, confirmed the importance of reactivated AR signaling in castration-resistant PC and validated important concepts that had been proposed in the field several decades ago but had remained so far unproven, including adrenal-targeted therapy and combined androgen blockade. The past decade has seen steady advances toward more comprehensive AR axis targeting. Now the question is raised whether we have accomplished the maximum AR axis inhibition possible or there is still room for improvement. This review, marking the 80-year anniversary of ADT and 10-year anniversary of successful ARSIs, examines their current clinical use and discusses future directions, in particular combination regimens, to maximize their efficacy, delay emergence of resistance and improve patient outcomes.
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http://dx.doi.org/10.1530/ERC-21-0098DOI Listing
July 2021

Re: Umang Swami, Pedro Isaacsson Velho, Roberto Nussenzveig, et al. Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer. Eur Urol 2020;78:652-6: Can Mutant SPOP Become an Actionable Biomarker for Precision Oncology Management of Prostate Cancer?

Eur Urol 2021 Mar 25;79(3):e91-e93. Epub 2020 Dec 25.

Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2020.12.012DOI Listing
March 2021

Discovery, Structure-Activity Relationship, and Biological Activity of Histone-Competitive Inhibitors of Histone Acetyltransferases P300/CBP.

J Med Chem 2020 05 21;63(9):4716-4731. Epub 2020 Apr 21.

Avera Institute for Human Genetics, Sioux Falls, South Dakota 57108, United States.

Histone acetyltransferase (HAT) p300 and its paralog CBP acetylate histone lysine side chains and play critical roles in regulating gene transcription. The HAT domain of p300/CBP is a potential drug target for cancer. Through compound screening and medicinal chemistry, novel inhibitors of p300/CBP HAT with their IC values as low as 620 nM were discovered. The most potent inhibitor is competitive against histone substrates and exhibits a high selectivity for p300/CBP. It inhibited cellular acetylation and had strong activity with EC of 1-3 μM against proliferation of several tumor cell lines. Gene expression profiling in estrogen receptor (ER)-positive breast cancer MCF-7 cells showed that inhibitor treatment recapitulated siRNA-mediated p300 knockdown, inhibited ER-mediated gene transcription, and suppressed expression of numerous cancer-related gene signatures. These results demonstrate that the inhibitor is not only a useful probe for biological studies of p300/CBP HAT but also a pharmacological lead for further drug development targeting cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340344PMC
May 2020

Prostate cancer research: The next generation; report from the 2019 Coffey-Holden Prostate Cancer Academy Meeting.

Prostate 2020 02 11;80(2):113-132. Epub 2019 Dec 11.

Science Department, Prostate Cancer Foundation, Santa Monica, California.

Introduction: The 2019 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Prostate Cancer Research: The Next Generation," was held 20 to 23 June, 2019, in Los Angeles, California.

Methods: The CHPCA Meeting is an annual conference held by the Prostate Cancer Foundation, that is uniquely structured to stimulate intense discussion surrounding topics most critical to accelerating prostate cancer research and the discovery of new life-extending treatments for patients. The 7th Annual CHPCA Meeting was attended by 86 investigators and concentrated on many of the most promising new treatment opportunities and next-generation research technologies.

Results: The topics of focus at the meeting included: new treatment strategies and novel agents for targeted therapies and precision medicine, new treatment strategies that may synergize with checkpoint immunotherapy, next-generation technologies that visualize tumor microenvironment (TME) and molecular pathology in situ, multi-omics and tumor heterogeneity using single cells, 3D and TME models, and the role of extracellular vesicles in cancer and their potential as biomarkers.

Discussion: This meeting report provides a comprehensive summary of the talks and discussions held at the 2019 CHPCA Meeting, for the purpose of globally disseminating this knowledge and ultimately accelerating new treatments and diagnostics for patients with prostate cancer.
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http://dx.doi.org/10.1002/pros.23934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301761PMC
February 2020

Multimodal action of ONECUT2 in driving neuroendocrine prostate cancer.

Transl Cancer Res 2019 Mar;8(Suppl 2):S198-S203

Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

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http://dx.doi.org/10.21037/tcr.2019.02.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662936PMC
March 2019

A Novel Mechanism to Drive Castration-Resistant Prostate Cancer.

Trends Endocrinol Metab 2018 06 28;29(6):366-368. Epub 2018 Mar 28.

Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Androgen receptor signaling is critical for prostate adenocarcinoma, even after androgen deprivation therapy. Persistence of intratumoral androgens has been found in castration-resistant prostate cancer and attributed to increased in situ synthesis. Recently, Sharifi and colleagues reported an additional mechanism that can enhance local androgenic exposure: downregulation of an androgen-inactivating enzyme.
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http://dx.doi.org/10.1016/j.tem.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960430PMC
June 2018

ICG-001 Exerts Potent Anticancer Activity Against Uveal Melanoma Cells.

Invest Ophthalmol Vis Sci 2018 01;59(1):132-143

Department of Ophthalmology, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, United States.

Purpose: Uveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/β-catenin-mediated transcriptional program.

Methods: We used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression. In vivo efficacy of ICG-001 was evaluated in a UM xenograft model.

Results: ICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice.

Conclusions: Using in vitro and in vivo experiments, we demonstrate that ICG-001 has strong anticancer activity against UM cells and suppresses transcriptional programs critical for the cancer cell. Our results suggest that ICG-001 holds promise and should be examined further as a novel therapeutic agent for UM.
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http://dx.doi.org/10.1167/iovs.17-22454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769500PMC
January 2018

Gatekeepers of chromatin: Small metabolites elicit big changes in gene expression.

Trends Biochem Sci 2012 Nov 1;37(11):477-83. Epub 2012 Sep 1.

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA.

Eukaryotes are constantly fine-tuning their gene expression programs in response to the demands of the environment and the availability of nutrients. Such dynamic regulation of the genome necessitates versatile chromatin architecture. Rapid changes in transcript levels are brought about via a wide range of post-translational modifications of the histone proteins that control chromatin structure. Many enzymes responsible for these modifications have been identified and they require various metabolic cofactors or substrates for their activity. Herein, we highlight recent developments that have begun to reveal particular cellular metabolites that might in fact be underappreciated regulators of gene expression through their ability to modulate particular histone modifications.
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http://dx.doi.org/10.1016/j.tibs.2012.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482309PMC
November 2012

Checkpoint genes and Exo1 regulate nearby inverted repeat fusions that form dicentric chromosomes in Saccharomyces cerevisiae.

Proc Natl Acad Sci U S A 2010 Dec 23;107(50):21605-10. Epub 2010 Nov 23.

Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA.

Genomic rearrangements are common, occur by largely unknown mechanisms, and can lead to human diseases. We previously demonstrated that some genome rearrangements occur in budding yeast through the fusion of two DNA sequences that contain limited sequence homology, lie in inverted orientation, and are within 5 kb of one another. This inverted repeat fusion reaction forms dicentric chromosomes, which are well-known intermediates to additional rearrangements. We have previously provided evidence indicating that an error of stalled or disrupted DNA replication forks can cause inverted repeat fusion. Here we analyze how checkpoint protein regulatory pathways known to stabilize stalled forks affect this form of instability. We find that two checkpoint pathways suppress inverted repeat fusion, and that their activities are distinguishable by their interactions with exonuclease 1 (Exo1). The checkpoint kinase Rad53 (Chk2) and recombination protein complex MRX(MRN) inhibit Exo1 in one pathway, whereas in a second pathway the ATR-like kinases Mec1 and Tel1, adaptor protein Rad9, and effector kinases Chk1 and Dun1 act independently of Exo1 to prevent inverted repeat fusion. We provide a model that indicates how in Rad53 or MRX mutants, an inappropriately active Exo1 may facilitate faulty template switching between nearby inverted repeats to form dicentric chromosomes. We further investigate the role of Rad53, using hypomorphic alleles of Rad53 and null mutations in Rad9 and Mrc1, and provide evidence that only local, as opposed to global, activity of Rad53 is sufficient to prevent inverted repeat fusion.
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http://dx.doi.org/10.1073/pnas.1001938107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003031PMC
December 2010

The role of replication bypass pathways in dicentric chromosome formation in budding yeast.

Genetics 2010 Dec 13;186(4):1161-73. Epub 2010 Sep 13.

Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721, USA.

Gross chromosomal rearrangements (GCRs) are large scale changes to chromosome structure and can lead to human disease. We previously showed in Saccharomyces cerevisiae that nearby inverted repeat sequences (∼20-200 bp of homology, separated by ∼1-5 kb) frequently fuse to form unstable dicentric and acentric chromosomes. Here we analyzed inverted repeat fusion in mutants of three sets of genes. First, we show that genes in the error-free postreplication repair (PRR) pathway prevent fusion of inverted repeats, while genes in the translesion branch have no detectable role. Second, we found that siz1 mutants, which are defective for Srs2 recruitment to replication forks, and srs2 mutants had opposite effects on instability. This may reflect separate roles for Srs2 in different phases of the cell cycle. Third, we provide evidence for a faulty template switch model by studying mutants of DNA polymerases; defects in DNA pol delta (lagging strand polymerase) and Mgs1 (a pol delta interacting protein) lead to a defect in fusion events as well as allelic recombination. Pol delta and Mgs1 may collaborate either in strand annealing and/or DNA replication involved in fusion and allelic recombination events. Fourth, by studying genes implicated in suppression of GCRs in other studies, we found that inverted repeat fusion has a profile of genetic regulation distinct from these other major forms of GCR formation.
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http://dx.doi.org/10.1534/genetics.110.122663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998301PMC
December 2010

Genetics. Replication error amplified.

Science 2010 Aug;329(5994):911-3

Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA.

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http://dx.doi.org/10.1126/science.1194261DOI Listing
August 2010

Fusion of nearby inverted repeats by a replication-based mechanism leads to formation of dicentric and acentric chromosomes that cause genome instability in budding yeast.

Genes Dev 2009 Dec;23(24):2861-75

Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721, USA.

Large-scale changes (gross chromosomal rearrangements [GCRs]) are common in genomes, and are often associated with pathological disorders. We report here that a specific pair of nearby inverted repeats in budding yeast fuse to form a dicentric chromosome intermediate, which then rearranges to form a translocation and other GCRs. We next show that fusion of nearby inverted repeats is general; we found that many nearby inverted repeats that are present in the yeast genome also fuse, as does a pair of synthetically constructed inverted repeats. Fusion occurs between inverted repeats that are separated by several kilobases of DNA and share >20 base pairs of homology. Finally, we show that fusion of inverted repeats, surprisingly, does not require genes involved in double-strand break (DSB) repair or genes involved in other repeat recombination events. We therefore propose that fusion may occur by a DSB-independent, DNA replication-based mechanism (which we term "faulty template switching"). Fusion of nearby inverted repeats to form dicentrics may be a major cause of instability in yeast and in other organisms.
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http://dx.doi.org/10.1101/gad.1862709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2800083PMC
December 2009

Human Schlemm's canal cells express the endothelial adherens proteins, VE-cadherin and PECAM-1.

Curr Eye Res 2002 Nov;25(5):299-308

Department of Surgery, The University of Arizona, Tucson, AZ, USA.

Purpose. The majority of resistance to outflow of aqueous humor resides at or near the inner wall of Schlemm's canal (SC). Transmembrane proteins that contribute to the generation of resistance to aqueous outflow likely participate in junctional complexes between SC cells. The purpose of the present study was to examine the expression of cadherins in SC cells that play a significant role in adherens junction complexes that control permeability of vascular endothelia. Methods. Identification of cadherin subtype mRNAs was examined by hybridization screening of three different SC cDNA libraries and by polymerase chain reaction analysis with degenerate primers. Expression of endothelial adherens proteins, vascular endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM-1), was examined by western blot analyses of whole cell lysates prepared from SC and trabecular meshwork cells and by immunofluorescence microscopy of frozen sections of human anterior chambers. As controls, bovine retinal, bovine aortic, human umbilical vein and human iliac vein endothelial cells were examined for VE-cadherin expression. Results. Screens of SC cDNAs revealed abundant expression of N-cadherin and VE-cadherin. Expression of VE-cadherin protein was identified in both inner and outer wall SC cells, appropriately localized to SC intercellular borders and appeared as a single band of approximately 130 kDa by western blot analysis. Specific labeling of PECAM-1 was similar to VE-cadherin and appeared as a single band of approximately 130 kDa by western blot analysis. Conclusions. VE-cadherin and PECAM-1 expression in SC suggests that SC cells are vascular in origin and contain adherens protein likely involved in restricting fluid flow across the inner wall of SC.
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http://dx.doi.org/10.1076/ceyr.25.5.299.13495DOI Listing
November 2002
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