scholarly journals Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention

2021 ◽  
Vol 22 (7) ◽  
pp. 3753
Author(s):  
Maria Teresa Vietri ◽  
Giovanna D’Elia ◽  
Gemma Caliendo ◽  
Marianna Resse ◽  
Amelia Casamassimi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Synthetic Lethality ◽  
Current Knowledge ◽  
Target Therapy ◽  
Parp Inhibitors ◽  
Cancer Type ◽  
Cancer Genes ◽  
Therapeutic Implications ◽  
Hereditary Prostate Cancer ◽  
Mmr Genes

Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.

scholarly journals PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 565 ◽  
Author(s):  
Virtanen ◽  
Paunu ◽  
Ahlskog ◽  
Varnai ◽  
Sipeky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Dna Repair ◽  
Therapeutic Potential ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Treatment Modalities ◽  
Cancer Type ◽  
Castration Resistance ◽  
Single Strand Break

Prostate cancer is globally the second most commonly diagnosed cancer type in men.Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

Use of serum and tissue biomarker analysis embedded in a phase II clinical trial of cytarabine in castration-refractory prostate cancer to investigate prostate cancer biology.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 59-59
Author(s):  
S. Niraula ◽  
U. Emmeneger ◽  
L. Adams ◽  
I. Tannock ◽  
S. S. Sridhar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Cancer Biology ◽  
Target Therapy ◽  
Phase Ii Clinical Trial ◽  
Mrna Levels ◽  
Cancer Genes ◽  
Biomarker Analysis ◽  
Grade 3

59 Background: Other than the androgen receptor, the TMPRSS2-ERG genomic aberrations in prostate cancer provide the first recent opportunity to target therapy in castration refractory prostate cancer (CRPC). We initiated a phase II clinical trial of cytarabine in docetaxel refractory CRPC on the basis of microarray, in vitro and case report evidence that cytarabine may be particularly effective in men harbouring abnormalities of the ERG oncogenes. Embedded in this clinical trial was the first use of blood mRNA levels of prostate cancer related genes as biomarkers of response and prognosis. Methods: Patients with docetaxel refractory progressive CRPC received intravenous cytarabine at doses between 1g/m2-0.25 g/m2 q3 weekly. Responses were defined according to PCWG2C. 10 patients were enrolled between June 2007 and January 2010. TMPRSS2:ERG, PSA and PCA3 mRNA copies in whole blood collected with PAXgene tubes at the beginning of each cycle and at trial termination were quantified using transcription-mediated amplification assays. The prototype TMPRSS2:ERG assay detects the gene fusion isoform TMPRSS2 exon1 to ERG exon4. Results: No patients demonstrated a serum PSA response (PCWG2C). The average number of cycles administered was 2.6. Significant toxicities including grade 3-4 thrombocytopenia (2) and grade 3-4 neutropenia (3). These toxicities necessitated several dose reductions in the protocol, however most patients were removed from trial for serum PSA progression alone. PCA3 and PSA mRNAs were detectable in 8/10 and 9/10 cases, respectively; there was no correlation between serum PSA and PCA3 or PSA mRNA copy levels in blood. Testing for TMPRSS2:ERG in blood was able to predict the presence or absence of the TMPRSS2-ERG rearrangement in 9/10 cases when compared to 3 colour FISH carried out on baseline biopsies/ prostatectomies (2/10 positive for Exon 4:Exon 1 deletion). Conclusions: Cytarabine administation is ineffective in docetaxel refractory CRPC. Blood mRNA levels of prostate cancer genes reveal novel aspects of prostate cancer biology and have implications for the understanding of circulating tumour cells. [Table: see text]

scholarly journals BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations

2021 ◽  
Vol 22 (23) ◽  
pp. 12628
Author(s):  
Sidrah Shah ◽  
Rachelle Rachmat ◽  
Synthia Enyioma ◽  
Aruni Ghose ◽  
Antonios Revythis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Synthetic Lethality ◽  
Genomic Analysis ◽  
Parp Inhibitors ◽  
Brca Mutations ◽  
Prostate Carcinogenesis ◽  
Damage Response ◽  
Treatment Considerations ◽  
Related Mortality

Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.

scholarly journals Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors

2019 ◽  
Vol 20 (12) ◽  
pp. 3100 ◽  
Author(s):  
Daniela Criscuolo ◽  
Francesco Morra ◽  
Riccardo Giannella ◽  
Aniello Cerrato ◽  
Angela Celetti
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Novel Biomarkers

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

Abstract A69: Identification of prostate cancer genes in the African American Hereditary Prostate Cancer (AAHPC) study

2011 ◽  
Author(s):  
Luisel J. Ricks-Santi ◽  
Tshela Mason ◽  
Muneer Abbas ◽  
Georgia M. Dunston ◽  
Supraja Kolluri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Cancer Genes ◽  
Hereditary Prostate Cancer

scholarly journals Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3467
Author(s):  
Albert Jang ◽  
Oliver Sartor ◽  
Pedro C. Barata ◽  
Channing J. Paller
Keyword(s):  
Prostate Cancer ◽  
Mechanism Of Action ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Gene Mutations ◽  
Parp Inhibitors ◽  
Cellular Level ◽  
Tumor Control ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Metastatic castration-resistant prostate cancer (mCRPC) is an incurable malignancy with a poor prognosis. Up to 30% of patients with mCRPC have mutations in homologous recombination repair (HRR) genes. Poly (ADP-ribose) polymerase (PARP) inhibitors take advantage of HRR deficiency to kill tumor cells based on the concept of synthetic lethality. Several PARP inhibitors (PARPis) have been successful in various malignancies with HRR gene mutations including BRCA1/2, especially in breast cancer and ovarian cancer. More recently, olaparib and rucaparib were approved for mCRPC refractory to novel hormonal therapies, and other PARPis will likely follow. This article highlights the mechanism of action of PARPis at the cellular level, the preclinical data regarding a proposed mechanism of action and the effectiveness of PARPis in cancer cell lines and animal models. The article expands on the clinical development of PARPis in mCRPC, discusses potential biomarkers that may predict successful tumor control, and summarizes present and future clinical research on PARPis in the metastatic disease landscape.

scholarly journals Moving beyond PARP Inhibition: Current State and Future Perspectives in Breast Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 7884
Author(s):  
Michela Palleschi ◽  
Gianluca Tedaldi ◽  
Marianna Sirico ◽  
Alessandra Virga ◽  
Paola Ulivi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Synthetic Lethality ◽  
Current Knowledge ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Breast Cancer Treatment ◽  
Parp Inhibition ◽  
Combination Strategies ◽  
Pubmed Search

Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms “PARP inhibitors” and “breast cancer”, was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.

Sign in / Sign up

Export Citation Format

Share Document