ABSTRACT
ABSTRACT: Acral lentiginous melanoma (ALM) is an aggressive type of cutaneous melanoma (CM) that arises on palms, soles, and nail units. ALM is rare in White population, but it is relatively more frequent in dark-skinned populations. There is an unmet need to develop new personalized and more effective treatments strategies for ALM. Increased expression of antiapoptotic proteins (ie, BCL2, MCL1) has been shown to contribute to tumorigenesis and therapeutic resistance in multiple tumor types and has been observed in a subset of ALM and mucosal melanoma cell lines in vivo and in vitro. However, little is known about their expression and clinical significance in patients with ALM. Thus, we assessed protein expression of BCL2, MCL1, BIM, and BRAF V600E by immunohistochemistry in 32 melanoma samples from White and Hispanic populations, including ALM and non-ALM (NALM). BCL2, MCL1, and BIM were expressed in both ALM and NALM tumors, and no significant differences in expression of any of these proteins were detected between the groups, in our relatively small cohort. There were no significant associations between protein expression and BRAF V600E status, overall survival, or ethnicity. In summary, ALM and NALM demonstrate frequent expressions of apoptosis-related proteins BCL2, MCL1, and BIM. Our findings suggest that patients with melanoma, including ALM, may be potential candidates for apoptosis-directed therapies.
Subject(s)
Apoptosis , Bcl-2-Like Protein 11 , Biomarkers, Tumor , Melanoma , Myeloid Cell Leukemia Sequence 1 Protein , Proto-Oncogene Proteins c-bcl-2 , Skin Neoplasms , Humans , Skin Neoplasms/pathology , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Male , Melanoma/pathology , Melanoma/genetics , Melanoma/metabolism , Female , Middle Aged , Aged , Proto-Oncogene Proteins c-bcl-2/metabolism , Bcl-2-Like Protein 11/metabolism , Bcl-2-Like Protein 11/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/analysis , Proto-Oncogene Proteins B-raf/genetics , Adult , Immunohistochemistry , Aged, 80 and overABSTRACT
BACKGROUND: Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer. METHODS: We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m2 and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868. FINDINGS: Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths. INTERPRETATION: Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned. FUNDING: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Taxoids/therapeutic use , Aged , Anemia/chemically induced , Anorexia/chemically induced , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Dehydration/chemically induced , Diarrhea/chemically induced , Fatigue/chemically induced , Humans , Hypokalemia/chemically induced , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Neutropenia/chemically induced , Progression-Free Survival , Prostatic Neoplasms, Castration-Resistant/pathology , Taxoids/administration & dosage , Thrombocytopenia/chemically inducedABSTRACT
BACKGROUND AND OBJECTIVE: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. METHODS: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, Subject(s)
Antibodies, Monoclonal, Humanized
, Cisplatin
, Feasibility Studies
, Neoadjuvant Therapy
, Neoplasm Invasiveness
, Nivolumab
, Urinary Bladder Neoplasms
, Humans
, Urinary Bladder Neoplasms/drug therapy
, Urinary Bladder Neoplasms/pathology
, Urinary Bladder Neoplasms/mortality
, Male
, Neoadjuvant Therapy/methods
, Female
, Aged
, Cisplatin/therapeutic use
, Cisplatin/administration & dosage
, Nivolumab/therapeutic use
, Middle Aged
, Antibodies, Monoclonal, Humanized/therapeutic use
, Antineoplastic Combined Chemotherapy Protocols/therapeutic use
, Cystectomy/methods
ABSTRACT
The dramatic recent advances in therapy of melanoma require a more personalized and precise diagnostic approach to aid in clinical decisions. Tissue-based biomarkers in pathology have diagnostic, prognostic and predictive relevance. Herein we review the most commonly used pathology-based biomarkers in melanoma. Most of these biomarkers are evaluated through immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) performed on formalin fixed paraffin embedded tissue (FFPE), and are widely available in clinical pathology laboratories. We describe the utility of MART1/Ki67, p16, PRAME, markers of lymphovascular invasion (D2-40, CD31, D2-40/MITF, CD31/SOX-10), BRAF V600E, NRAS, KIT, BAP1, ALK, NTRK, PD-L1, TERT, PTEN, iNOS, and MMR proteins (MLH1, MSH2, MSH6, PMS2) in the evaluation of melanoma specimens. Correct interpretation and awareness of the significance of these biomarkers is crucial for pathologists, dermatologists, and oncologists who take care of melanoma patients.
Subject(s)
Biomarkers, Tumor/metabolism , Decision Making/ethics , Immunohistochemistry/methods , In Situ Hybridization, Fluorescence/methods , Melanoma/diagnosis , Decision Making/physiology , Female , Humans , Male , Melanoma/pathologyABSTRACT
PURPOSE: Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant prostate cancer models. EXPERIMENTAL DESIGN: Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer. RESULTS: We studied two cell line-derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and PTEN loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like (SPOPL) gene in PDXs derived from seven human donors of 28 studied (25%). SPOPL is a SPOP paralog, and SPOP mutations define a molecular subclass of prostate cancer. SPOPL deletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development. CONCLUSIONS: The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer-specific, marker-driven therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Biomarkers, Tumor/genetics , Precision Medicine/methods , Prostatic Neoplasms/drug therapy , Adaptor Proteins, Vesicular Transport/genetics , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Comparative Genomic Hybridization , DNA Copy Number Variations , Humans , Male , Mice , Primary Cell Culture , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Sequence Deletion , Xenograft Model Antitumor Assays/methodsABSTRACT
Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status.
Subject(s)
Naphthalenes/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Receptors, Androgen/metabolism , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Triazoles/administration & dosage , Abiraterone Acetate/administration & dosage , Androgens/biosynthesis , Animals , Biopsy , Cell Line, Tumor , Dehydroepiandrosterone/chemistry , Humans , Hydrocortisone/blood , Male , Mass Spectrometry , Mice , Mice, SCID , Neoplasm Transplantation , Precision Medicine , Prednisone/administration & dosage , Receptors, Androgen/genetics , Signal Transduction , Steroid 17-alpha-Hydroxylase/metabolismABSTRACT
White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression.
Subject(s)
Cell Movement/physiology , Chemokine CXCL1/metabolism , Mesenchymal Stem Cells/pathology , Obesity/pathology , Prostatic Neoplasms/pathology , Tumor Microenvironment/physiology , Actins/metabolism , Adipocytes/pathology , Adipose Tissue, White/cytology , Adipose Tissue, White/pathology , Adult , Aged , Aged, 80 and over , Animals , Cell Line, Tumor , Chemokine CXCL1/genetics , Diet, High-Fat/adverse effects , Disease Progression , Endothelial Cells/pathology , Humans , Interleukin-8/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Nude , Middle Aged , Neovascularization, Pathologic/pathology , Obesity/complications , Obesity/metabolism , Primary Cell Culture , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/complications , RNA, Small Interfering/metabolism , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/metabolism , Tissue Array Analysis , Xenograft Model Antitumor AssaysABSTRACT
UNLABELLED: The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP-TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5-CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer. SIGNIFICANCE: We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo-YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5-CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival.
Subject(s)
Chemokine CXCL5/genetics , Myeloid Cells/immunology , PTEN Phosphohydrolase/deficiency , Prostatic Neoplasms/immunology , Smad4 Protein/deficiency , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line, Tumor , Chemokine CXCL5/metabolism , Disease Progression , Hippo Signaling Pathway , Humans , Male , Mice , Phosphoproteins/genetics , Phosphoproteins/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/metabolism , Signal Transduction , Transcription Factors , YAP-Signaling ProteinsABSTRACT
BACKGROUND: In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride. METHODS: From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERß, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers. FINDINGS: We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups. INTERPRETATION: We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT.
Subject(s)
Finasteride/administration & dosage , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Receptors, Androgen/metabolism , Administration, Oral , Aged , Apoptosis , Biomarkers, Tumor/metabolism , Cell Proliferation/drug effects , Double-Blind Method , Finasteride/pharmacology , Humans , Logistic Models , Male , Middle Aged , Neoplasm Grading , Prostatic Neoplasms/metabolism , Treatment OutcomeABSTRACT
BACKGROUND: Human T-lymphotropic virus (HTLV)-1-associated infective dermatitis (ID) is a rare severe chronic eczema, considered as a harbinger for the development of cutaneous adult T-cell leukemia/lymphoma (ATLL) and/or HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The pathogenesis of ID remains unclear. High numbers of peripheral blood CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) have been reported in ATLL and HAM/TSP. OBJECTIVE: To investigate the status of Tregs, unknown to date, and the histopathological features of ID. METHODS: We studied 16 skin biopsies from 15 Peruvian adults and children with ID by immunohistochemistry. RESULTS: Histopathological patterns were seborrheic dermatitis-like and lichenoid. Intraepidermal lymphocytes were conspicuous. The infiltrate was composed of a CD3+ T cell infiltrate with a predominance of CD8+ over CD4+ cells. CD4+ CD25+ FoxP3+ Tregs were rare and their numbers were significantly lower than those reported in other inflammatory dermatoses. CONCLUSION: Tregs have an essential role in maintaining immune homeostasis of skin. Treg dysregulation ends in severe clinical manifestations. The clinical presentation of ID, with lesions resembling those seen in patients with atopic dermatitis and with mutations in the FoxP3 gene, is in agreement with a common Treg-deficient skin environment in these disorders, possibly secondary to HTLV-1 infection.
Subject(s)
Eczema/immunology , Forkhead Transcription Factors/analysis , HTLV-I Infections/immunology , Human T-lymphotropic virus 1 , Skin Diseases, Viral/immunology , T-Lymphocytes, Regulatory/chemistry , Adolescent , Adult , Aged , Aged, 80 and over , CD3 Complex/analysis , CD4-CD8 Ratio , Child , Child, Preschool , Chronic Disease , Eczema/pathology , Eczema/virology , Female , HTLV-I Infections/pathology , Humans , Male , Middle Aged , Skin Diseases, Viral/pathology , Young AdultABSTRACT
Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Prostatic Neoplasms/pathology , Quinolones/therapeutic use , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Benzimidazoles/pharmacology , Bone Neoplasms/pathology , Bone and Bones/drug effects , Bone and Bones/metabolism , Cell Line, Tumor , Disease Models, Animal , Fibroblast Growth Factor 2/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Osteoblasts/drug effects , Osteoblasts/metabolism , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Quinolones/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Stromal Cells/drug effects , Stromal Cells/pathology , Tumor Microenvironment/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Androgen deprivation is the standard treatment for advanced prostate cancer (PCa), but most patients ultimately develop resistance and tumor recurrence. We found that MYB is transcriptionally activated by androgen deprivation therapy or genetic silencing of the androgen receptor (AR). MYB silencing inhibited PCa growth in culture and xenografts in mice. Microarray data revealed that c-Myb and AR shared a subset of target genes that encode DNA damage response (DDR) proteins, suggesting that c-Myb may supplant AR as the dominant regulator of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures including AR, MYB, and their common DDR-associated target genes positively correlated with metastasis, castration resistance, tumor recurrence, and decreased survival in PCa patients. In culture and in xenograft-bearing mice, a combination strategy involving the knockdown of MYB, BRCA1, or TOPBP1 or the abrogation of cell cycle checkpoint arrest with AZD7762, an inhibitor of the checkpoint kinase Chk1, increased the cytotoxicity of the poly[adenosine 5'-diphosphate (ADP)-ribose] polymerase (PARP) inhibitor olaparib in PCa cells. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the DDR pathway involving c-Myb, TopBP1, ataxia telangiectasia mutated- and Rad3-related (ATR), and Chk1.