Sarki A. Abdulkadir's research while affiliated with Northwestern University and other places

Publications (137)

Article
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Introduction: Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), promotes cell death in preclinical models of aggressive prostate cancer. We hypo...
Article
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Inflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate. Using clinical samples of men with I...
Article
Androgen receptor pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance is common. Here, we used a CRISPR activation screen to identify genes that promote enzalutamide resistance in the metastatic castration-sensitive prostate cancer cell line LNCaP. We found that activation of the TGF-β target gene, PRRX2, prom...
Article
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In the original version of this article unfortunately references [34–40] are missing: The original article has been corrected. © The Author(s), under exclusive licence to Springer Nature Limited 2021
Article
MYC regulates multiple gene programs, raising questions about the potential selectivity and downstream transcriptional consequences of MYC inhibitors as cancer therapeutics. Here, we examined the effect of a small-molecule MYC inhibitor, MYCi975, on the MYC/MAX cistromes, epigenome, transcriptome, and tumorigenesis. Integrating these data revealed...
Article
Androgen receptor (AR) pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance to therapy is common. Here, we used a CRISPR activation screen in metastatic castration-sensitive prostate cancer cells to identify genes that promote resistance to AR inhibitors. Activation of the TGFβ target gene paired-related homeob...
Article
84 Background: Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Expression of EphB4 is increased in prostate cancer tissue and cell lines and retained in castration resistant states, and can promote cell migration, invasion, and metastases. Blocking the EphB4-EphrinB2 pat...
Article
Background The metabolism of normal prostate relies on glycolysis, with prostate cancer having reduced glycolysis and increased aerobic metabolism. Advanced glycation end products (AGEs) accumulate in tissues as a result of age and glycolytic rate. Differential AGE levels were recently observed in prostate cancer tissues. Herein we sought to quanti...
Article
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Men with early-onset prostate cancer are at increased risk for cancer-related mortality, yet the prevalence and spectrum of molecular alterations in this patient population is unknown. Here, we analyze comprehensive genomic profiling data to characterize the molecular drivers of early-onset prostate cancer in patients with clinically advanced and m...
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Forkhead box protein A1 (FOXA1) is essential for androgen-dependent prostate cancer (PCa) growth. However, how FOXA1 levels are regulated remains elusive and its therapeutic targeting proven challenging. Here, we report FOXA1 as a nonhistone substrate of enhancer of zeste homolog 2 (EZH2), which methylates FOXA1 at lysine-295. This methylation is r...
Article
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis, and there is a critical need for novel therapeutic approaches. NEPC is associated with molecular perturbation of several pathways, including amplification of MYCN. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the path...
Article
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Genetic coessentiality analysis, a computational approach which identifies genes sharing a common effect on cell fitness across large-scale screening datasets, has emerged as a powerful tool to identify functional relationships between human genes. However, widespread implementation of coessentiality to study individual genes and pathways is limite...
Article
MYC is a highly validated oncogenic transcription factor and cancer target. However, the disordered nature of this protein has made it a challenging target, with no clinical stage, direct small-molecule MYC inhibitors available. Recent work leveraging a large in silico chemical library and a rapid in vivo screen has expanded the chemotypes of direc...
Article
The risk factors for prostate cancer include a high‐fat diet and obesity, both of which are associated with an altered cell environment including increased inflammation. It has been shown that chronic inflammation due to a high‐fat diet or bacterial infection has the potential to accelerate prostate cancer as well as its precursor, prostatic intrae...
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The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostate cancer (PCa) is undefined. Here we show that DOT1L is overexpressed in PCa and is associated with poor outcome. Genetic and chemical inhibition of DOT1L selectively impaire...
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Purpose: African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic st...
Article
e17517 Background: Although PCa incidence has stabilized/decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years-old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years-old. Studies have described genetic abnormalities in aggressive localized or...
Article
e17534 Background: PIM kinases are highly expressed in high risk prostate cancer and are associated with aggressiveness and poor prognosis, presenting a therapeutic target. Methods: We studied PIM inhibition (PIMi) in both hormone-dependent (LNCaP) and -independent (DU145, 22Rv1) prostate cancer cell lines and mouse xenografts. We evaluated PIMi ef...
Article
Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. We studied 218,084 men in the population‐based UK Biobank cohort, aged 40‐69 at study entry between 2006 and 2010, with follow‐up through mid‐2015. We asses...
Article
TPS274 Background: The EphB4/EphrinB2 pathway is a promising therapeutic target for patients with mCRPC. EphB4 expression is increased in prostate cancer tissue and cell lines, and retained in castration resistant states. EphB4 crosstalks with the PI3K/AKT and MAPK pathways to regulate cell survival and proliferation, and its interaction with the t...
Preprint
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Background: Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. Objective: To test the association between IBD with incident PC. Design, setting, and participants: We studied 218,084 men in the population-bas...
Article
Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylati...
Article
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The EPHB4 receptor is implicated in the development of several epithelial tumors and is a promising therapeutic target, including in prostate tumors in which EPHB4 is overexpressed and promotes tumorigenicity. Here, we show that high expression of EPHB4 correlated with poor survival in prostate cancer patients and EPHB4 inhibition induced cell deat...
Article
Context Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that anti-tumor immune responses can be elicited in ACC have fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab. Objective The primary endpoint was objective response rate accordi...
Conference Paper
Small molecules MYC inhibitors that are efficacious and tolerated will provide invaluable chemical probes and potential therapeutic agents. We have used in silico screening coupled to a rapid screen in mice to develop a series of novel small molecule MYC inhibitors (MYCi) which engage MYC inside cells, disrupt MYC/MAX heterodimerization and inhibit...
Article
TPS333 Background: Although PCa incidence has stabilized or decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years old. These observations are supported by data from 3 randomized trials. I...
Article
178 Background: Despite advances in therapy, metastatic prostate cancer (mPCA) remains lethal. Younger men with mPCA have a significantly greater risk of mPCA-related death compared to men diagnosed later in life. This suggests that early-onset mPCA is a uniquely aggressive subtype of disease, however, the genomic drivers have not been explored. He...
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Epidemiological and preclinical data suggest that antioxidants are protective against prostate cancer whose pathogenesis has been linked to oxidative stress. However, the selenium and vitamin E Cancer Prevention Trial (SELECT), found no efficacy for selenium in reducing prostate cancer incidence while vitamin E was associated with an increased risk...
Data
Video S9. PrS Cell at day 7 in Co-culture Exhibiting Pseudopodia Expansion and Contraction, and Remodeling of the Surrounding Matrix, Related to Figure 4 Cells used, PrE-1 and PrS mix 1.
Article
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The fibromuscular stroma of the prostate regulates normal epithelial differentiation and contributes to carcinogenesis in vivo. We developed and characterized a human 3D prostate organoid co-culture model that incorporates prostate stroma. Primary prostate stromal cells increased organoid formation and directed organoid morphology into a branched a...
Data
Video S1. Organoid at Day 7 in Co-culture Exhibiting Branching Morphogenesis, Related to Figure 1 Cells used, PrE-1 and PrS mix 1.All movies are composed of time-lapse images taken every 5 min. Time format, hour:min.
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Video S10. Organoid Co-cultured with GFP-Labeled Mouse Embryonic Fibroblasts (NIH3T3 Cells), Related to Figure 4 Extensive Cell-Cell Contact and Encapsulation of Organoids Inhibited Branching. Cells used, PrE-1.
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Video S4. Stromal Cell (Bottom Left) Taxis toward an Organoid and Subsequent Influence on Organoid Budding and Branching Distal to Stroma-Organoid Contact, Related to Figure 4 Cells used, PrE-1 and PrS mix 1.
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Video S2. Organoid at Day 7 in Mono-culture Exhibiting Branching Morphogenesis, Related to Figure 1 Cells used, PrE-1.
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Video S5. Stromal Cell Pseudopodia Extension (Bottom Right) and Direct Contact with an Organoid, Related to Figure 4 Subsequent Bud Formation and Elongation Occurred Distal to Stroma-Organoid Contact. Cells used, PrE-1 and PrS mix 1.
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Video S3. Stromal Cell (Right) Taxis toward a Branching Organoid (Left) in Co-culture, Related to Figure 4 Cells used, PrE-1 and PrS mix 1.
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Video S6. Stromal Cells (Top Right) in Direct Contact and Migrating with a Branched Organoid, Related to Figure 4 Complex Stalk Elongation Occurred Distal to Stroma-Organoid Contact. Cells used, PrE-1 and PrS mix 1.
Data
Video S7. Organoid in Co-culture Exhibiting Complex Branching Morphogenesis, Related to Figure 4 Bud Detachment Occurred after 29 h (Top of Organoid), and Stalk Detachment at 31 h (Top of Frame). Cells used, PrE-1 and PrS mix 1.
Data
Video S8. Organoid Co-cultured with GFP-Labeled PrS Cells Integrated with More Complex Organoid Structures, Related to Figure 4 Cells used, PrE-1 and PrS mix 3.
Article
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Prostate cancer (PC) progressed to castration resistance (CRPC) is a fatal disease. CRPC tumors develop resistance to new-generation antiandrogen enzalutamide through lineage plasticity, characterized by epithelial-mesenchymal transition (EMT) and a basal-like phenotype. FOXA1 is a transcription factor essential for epithelial lineage differentiati...
Article
The chromenone core is an ubiquitous group in biologically active natural products and has been extensively used in organic synthesis. Fluorine-derived compounds, including those with a trifluoromethyl group (CF3), have shown enhanced biological activities in numerous pharmaceuticals compared with their non-fluorinated analogues. 2-Trifluoromethylc...
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PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that reve...
Article
Background: Recurrence following androgen-deprivation therapy is associated with adverse clinical outcomes in prostate cancer, but the cellular origins and molecular mechanisms underlying this process are poorly defined. We previously identified a population of castration-resistant luminal progenitor cells expressing Bmi1 in the normal mouse prost...
Article
The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and this histone mark is associated with activation of gene expression. DOT1L has a well-known role in MLL fusion leukemogenesis, however, its role in prostate cancer is yet to be elucidated. Here we show that DOT1L is overexpressed in many solid tumors including prostate...
Article
Introduction: Recurrence is associated with mortality in prostate cancer, but the cellular origins and molecular mechanisms that drive this process have not been well-defined. An emerging model of resistance to androgen deprivation therapy (ADT) in prostate cancer, particularly to the more potent newer drugs, involves lineage plasticity or transdif...
Article
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Immune checkpoint inhibitors have not been effective for immunologically "cold" tumors, such as prostate cancer, which contain scarce tumor infiltrating lymphocytes. We hypothesized that select tissue-specific and immunostimulatory bacteria can potentiate these immunotherapies. Here we show that a patient-derived prostate-specific microbe, CP1, in...
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Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies but its role in SCCP has not been documented. We describe a patient wit...
Article
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Orthotopic tumor modeling is a valuable tool for pre-clinical prostate cancer research, as it has multiple advantages over both subcutaneous and transgenic genetically engineered mouse models. Unlike subcutaneous tumors, orthotopic tumors contain more clinically accurate vasculature, tumor microenvironment, and responses to multiple therapies. In c...
Article
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Vitamin E increased prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) through unknown mechanisms while Selenium showed no efficacy. We determined the effects of the SELECT supplements on benign (primary), premalignant ( RWPE-1) and malignant (LNCaP) prostate epithelial organoids. While the supplements decreased pro...
Article
Prostate cancer is the most common cancer among men, other than skin cancer, in the United States. When the cancer enters into the metastatic castration resistant stage (mCRPC), few treatment options are currently available and the disease is considered incurable. The purpose of this study is to investigate a new, targeted therapy against prostate...
Article
Androgen deprivation therapy is an efficient first line therapy for advanced prostate cancer. However, in most cases resistance inevitably develops resulting in metastatic castration-resistant prostate cancer (mCRPC). Abiraterone and enzalutamide are approved to treat mCRPC and act by inhibiting androgen biosynthesis and androgen receptor (AR) sign...
Article
Bone metastases are present in up to 70% of advanced prostate and breast cancers and occur at significant rates in a variety of other cancers. Bone metastases can be associated with significant morbidity. The establishment of bone metastasis activates several immunosuppressive mechanisms. Hence, understanding the tumor-bone microenvironment is cruc...
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Genomic studies are rapidly identifying genetic alterations in human cancer, but functional validation of such alterations has been slow. Here, using human prostate cancer as a model, we have assessed the feasibility of engineering defined genetic alterations in well-known cancer driver genes to transform benign prostate epithelial organoids derive...
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Identification of defined cell populations with stem/progenitor properties is key for understanding prostate development and tumorigenesis. Here we show that the polycomb repressor protein Bmi1 marks a population of castration-resistant luminal epithelial cells enriched in the mouse proximal prostate. We employ lineage tracing to show that these ca...
Data
Supplementary Figures 1-4, Supplementary Tables 1-5 and Supplementary Methods.
Article
Androgen receptor (AR) plays pivotal roles in prostate cancer. Upon androgen stimulation, AR recruits the PKN1 kinase, which phosphorylates histone H3 at threonine 11 (H3T11P), with subsequent recruitment of WDR5 and the SET1/MLL histone methyltransferase (HMTase) complex to promote AR target gene activation and prostate cancer cell growth. However...
Article
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PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence. A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were trea...
Article
Treatment of muscle invasive urothelial bladder carcinoma (BCa) remains a major challenge. Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets. This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa. Small molecule p...
Article
NKX3.1 is an androgen-regulated prostate tumor suppressor protein. We previously found that antioxidant administration (N-acetylcysteine) in the Nkx3.1 knock-out mouse model promoted prostate epithelial proliferation, suggesting that NKX3.1 activity modifies the effect of antioxidant administration on prostate carcinogenesis. Interestingly, adminis...
Article
SIRT3 is a genomically expressed, mitochondrial localized tumor suppressor protein where it directs multiple metabolic processes by deacetylating downstream protein substrates. Genetic deletion of Sirt3 in mice leads to the spontaneous development of mammary tumors starting at one year and decreased SIRT3 mRNA has been observed in several human tum...