scholarly journals Genetics of Prostate Carcinoma

2021 ◽  
Vol 50 (1) ◽  
pp. 71
Author(s):  
Božo Krušlin ◽  
Lucija Škara ◽  
Tonći Vodopić ◽  
Borna Vrhovec ◽  
Jure Murgić ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Carcinoma ◽  
Poor Prognosis ◽  
Large Scale ◽  
Metastatic Prostate Cancer ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Genomic Studies ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

<p>The aim of this review is to provide a brief overview of some current approaches regarding diagnostics, pathologic features, treatment, and genetics of prostate carcinoma (PCa). Prostate carcinoma is the most common visceral tumor and the second most common cancer-related cause of death in males. Clinical outcomes for patients with localized prostate cancer are excellent, but despite advances in prostate cancer treatments, castrate-resistant prostate cancer and metastatic prostate cancer patients have a poor prognosis. Advanced large-scale genomic studies revealed a large number of genetic alterations in prostate cancer. The meaning of these alterations needs to be validated in the specific prostate cancer molecular subtype context. Along these lines, there is a critical need for establishing genetically engineered mouse models, which would include speckle type BTB/POZ protein and isocitrate Dehydrogenase (NADP (+)) 1 mutant, as well as androgen receptor neuroendocrine subtypes of prostate cancer. Another urgent need is developing highly metastatic prostate cancer models, as only up to 17% of available models dis- play bone metastases and exhibit a less typical neuroendocrine prostate cancer or sarcomatoid carcinoma. Moreover, androgen deprivation and relapse should be mimicked in the genetically engineered mouse models, as androgen independence may yield a better model for metastatic castrate-resistant prostate cancer. The development of such refined animal models should be guid- ed by comparative genomics of primary versus corresponding metastatic tumors. Such an approach will have the potential to illuminate the key genetic events associated with specific molecular prostate cancer subsets and indicate directions for effective therapy.</p><p><strong>Conclusion</strong>. Despite excellent results in the treatment of localized prostatic carcinoma, castrate-resistant prostate can- cer and metastatic prostate cancer have a poor prognosis. Advanced large-scale genomic studies revealed a large number of ge- netic alterations in PCa. Experimental models of prostate carcinoma in genetically modified mice could provide new data about the genetic changes in such cancers and help in developing better animal models for treatment resistant prostate carcinomas.</p>

scholarly journals WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

2016 ◽  
Vol 23 (11) ◽  
pp. T85-T108 ◽  
Author(s):  
Damien A Leach ◽  
Sue M Powell ◽  
Charlotte L Bevan
Keyword(s):  
Prostate Cancer ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Current Knowledge ◽  
Transcriptional Responses ◽  
Number Variation ◽  
Genomic Studies ◽  
Life Threatening ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease – hence the quest for new effective therapies for ‘castrate-resistant’ prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions has identified several other nuclear receptor signalling pathways as potential drivers or modulators of CRPC.The nuclear receptors constitute a large (48 members) superfamily of transcription factors sharing a common modular functional structure. Many of them are activated by the binding of small lipophilic molecules, making them potentially druggable. Even those for which no ligand exists or has yet been identified may be tractable to activity modulation by small molecules. Moreover, genomic studies have shown that in models of CRPC, other nuclear receptors can potentially drive similar transcriptional responses to the androgen receptor, while analysis of expression and sequencing databases shows disproportionately high mutation and copy number variation rates among the superfamily. Hence, the nuclear receptor superfamily is of intense interest in the drive to understand how prostate cancer recurs and how we may best treat such recurrent disease. This review aims to provide a snapshot of the current knowledge of the roles of different nuclear receptors in prostate cancer – a rapidly evolving field of research.

scholarly journals Management of Advanced and Metastatic Prostate Cancer: A Need for a Sub-Saharan Guideline

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Ayun Cassell ◽  
Bashir Yunusa ◽  
Mohamed Jalloh ◽  
Medina Ndoye ◽  
Mouhamadou M. Mbodji ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Metastatic Prostate Cancer ◽  
Cost Effective ◽  
Androgen Deprivation ◽  
Sub Saharan Africa ◽  
International Agency ◽  
Castrate Resistant Prostate Cancer ◽  
Sub Saharan ◽  
Castrate Resistant

The estimated incidence rate of prostate cancer in Africa was 22.0/100,000 in 2016. The International Agency for Research on Cancer (IARC) has cited prostate cancer as a growing health threat in Africa with approximated 28,006 deaths in 2010 and estimated 57,048 deaths in 2030. The exact incidence of advanced and metastatic prostate cancer is not known in sub-Saharan Africa. Hospital-based reports from the region have shown a rising trend with most patients presenting with advanced or metastatic disease. The management of advanced and metastatic prostate cancer is challenging. The available international guidelines may not be cost-effective for an African population. The most efficient approach in the region has been surgical castration by bilateral orchidectomy or pulpectomy. Medical androgen deprivation therapy is expensive and may not be available. Patients with metastatic castrate-resistant prostate cancer tend to be palliated due to the absence or cost of chemotherapy or second-line androgen deprivation therapy in most of Africa. A cost-effective guideline for developing nations to address the rising burden of advanced prostate cancer is warranted at this moment.

Patterns of response to androgen deprivation therapy in younger patients with locally advanced or metastatic prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 324-324
Author(s):  
Matthew Keating ◽  
Lisa Giscombe ◽  
Andre Desouza ◽  
Shiva Kumar Reddy Mukkamalla ◽  
Ritesh Rathore
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Androgen Deprivation Therapy ◽  
Metastatic Prostate Cancer ◽  
Locally Advanced ◽  
Androgen Deprivation ◽  
Standards Of Care ◽  
National Cancer Database ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

324 Background: Androgen deprivation therapy (ADT) remains a standard of care in the treatment of locally advanced prostate cancer. But thanks to a few key trials (STAMPEDE, CHAARTED, and LATITUDE) reported within the past three years, docetaxel and abiraterone now have roles in extending overall survival in a patient population traditionally treated with ADT alone. These treatments when combined with ADT have been shown to extend overall survival in metastatic hormone-sensitive prostate cancer patients. The role of ADT in relation to other therapies continues to evolve rapidly. We intend to revisit ADT’s longstanding role in prostate cancer treatment using a national cancer database. Our aim is to look beyond traditional standards of care to identify patients more likely to have overall survival benefit from ADT. Are there any subgroups of patients with intermediate or high risk disease that have improved survival outcomes with androgen deprivation therapy, besides patients with localized disease that underwent radiation? Could there be other variables besides PSA and localization of the prostate cancer that should be considered when identifying ADT treatment candidates, or identifying survival trends in these groups? Methods: We are currently analyzing variables present in the National Cancer Database to retrospectively identify predictive factors for overall survival and progression to metastatic castrate resistant prostate cancer in locally advanced prostate cancers treated with ADT. We will evaluate time-to-death from the initiation of ADT and from the diagnosis of metastatic castrate resistant prostate cancer. The following variables in localized, locally advanced, and metastatic prostate cancer will be analyzed with Statistical Analysis Software: age, locally advanced, site-specific metastasis (M1a, M1b, M1c), Gleason score, local treatment (radical prostatectomy or radiation), stage (T, N, and M), prostate lobe (one vs. both; T2a/b vs. T2c), chemotherapy (date, time from M1 stage), comorbidity score, ethnicity, facility type, insurance, and risk groups (low/intermediate/high as per NCCN guidelines).

Immunogenomic landscape of neuroendocrine small cell prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 217-217
Author(s):  
Lucia Nappi ◽  
Claudia Kesch ◽  
Sepideh Vahid ◽  
Ladan Fazli ◽  
Bernhard J. Eigl ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Poor Prognosis ◽  
De Novo ◽  
Small Cell ◽  
Expression Intensity ◽  
Whole Exome ◽  
Castrate Resistant Prostate Cancer ◽  
Cd56 Expression ◽  
Castrate Resistant ◽  
Benign Prostate

217 Background: Neuroendocrine small cell prostate cancer (NEPC) is a lethal variant of prostate cancer (PCa) unresponsive to hormone therapy and associated with poor prognosis. Cisplatin induces short-lived responses and therefore alternative novel therapeutic options are urgently needed. Methods: Prostate specimens from radical prostatectomy or transurethral resection (benign prostate specimens n = 4, primary untreated or neoadjuvant hormone-treated adenocarcinoma n = 30, castrate-resistant prostate cancer-CRPC n = 38 and NEPC n = 16) were evaluated for PD-L1 (SpringBio, M4420), AR, chromogranin A, synaptophysin, NSE and CD56 expression by immunohistochemistry (IHC). Archival tissue from liver, lymph nodes and prostate from 30 additional patients with de novo and treatment emergent NEPC were analyzed for PD-L1 expression by IHC. The intensity was assessed as percentage of positive cells / mm2 of tissue. Targeted and whole exome sequencing of the high-density tumor areas were performed and correlated to the PD-L1 status (PD-L1+ve: > 1% of positive cells). OS was calculated from the date of diagnosis of NEPC to death. We set out to define PD-L1 expression and immunogenomic characteristics of NEPC. Results: PD-L1 was expressed in 0%, 5%, 10% and 41% of benign, adenocarcinoma, CRPC and NEPC specimens, respectively. The PD-L1 expression intensity was significantly higher in patients with NEPC (mean: 40%, range: 5-100%) compared to benign, adenocarcinoma and CRPC samples (mean: 0%, 2% and 8%, respectively, P < 0.0001). There was a higher prevalence of biallelic DNA Repair Defects (DRD) in the PD-L1+ve vs PD-L1-ve patients (65% vs 0%, P = 0.005). The median OS of the NEPC patients was 8.5 months vs 10.5 months in PD-L1+ve vs PD-L1-ve tumors (HR 1.24, 95% CI: 0.59-2.75, p = 0.55). Conclusions: NEPC have greater PD-L1 expression than adenoCa and CRPC. Biallelic DRD was exclusively observed in PD-L1+ve patients. Since PD-L1 expression and DRD have been associated to response to PARP and PD1/PD-L1 inhibitors in prostate and other cancers, further studies evaluating the activity of those agents in NEPC patients are warranted.

Olaparib for the treatment of metastatic prostate cancer

2021 ◽  
Author(s):  
Corinne Maurice Dror ◽  
Alexander W Wyatt ◽  
Kim N Chi
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Metastatic Prostate Cancer ◽  
Additional Treatment ◽  
Parp Inhibition ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Molecular Landscape

Recent innovations in the treatment of metastatic prostate cancer have improved patient outcomes. Nonetheless, this disease remains fatal and additional treatment approaches are needed. Greater understanding of the molecular landscape of metastatic prostate cancer has revealed recurrent alterations in key pathways amenable to therapeutic targeting. One such pathway is DNA repair, particularly alterations in genes directly or indirectly associated with homologous recombination repair found in up to one-quarter of patients with metastatic castrate-resistant prostate cancer (mCRPC). Olaparib, an inhibitor of poly-ADP-ribose polymerase, has recently gained approval for the treatment of mCRPC harboring alterations in homologous recombination repair genes. This review will provide a summary of evidence regarding PARP inhibition in the treatment of mCRPC, with a specific focus on olaparib.

Testing a prognostic model in patients with metastatic castrate resistant prostate cancer (MCRPC) treated prechemotherapy with abiraterone.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 283-283
Author(s):  
Shermaine Pan ◽  
Kellati Prasad ◽  
Emma Hall ◽  
Ric Swindell ◽  
Natalie Charnley
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Prognostic Model ◽  
Prognostic Models ◽  
Independent Group ◽  
Treatment Pathways ◽  
Number Of Patients ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

283 Background: There is a need for prognostic models in metastatic prostate cancer to determine optimal treatment pathways on development of castrate resistance. Abiraterone is an androgen biosynthesis inhibitor. Efficacy was proven in patients with MCRPC prechemotherapy in the COU-AA-302 trial with PSA PFS 11.1 months (Raj et al New Eng J med 2013). We have previously investigated prognostic factors in MCRPC (Charnley et al J Clin Oncol 2014). We reported a prognostic model which predicts that if alk phos rise ≥100 in the preceding 3 months and/or Hb<11 there is no response. The model was correct in 78.9% of responders and 55% of non responders (overall 66.7%). We test the model in an independent group of 81 patients prechemotherapy, some from a different treating centre. Methods: 81 patients with metastatic CRPC received abiraterone 1g daily prechemotherapy. Response to abiraterone was defined as a 50% reduction in PSA. Alk phos rise ≥100 in the previous 3 months and Hb<11 were related to PSA response. Results: 19 patients had both alk phos rise ≥100 in the preceding 3 months, and Hb<11. None of these patients had a PSA response. For the 31 patients with no risk factors 66% of cases responded. The predictive model was correct in 66% of true responders, and 85.3% of non responders, 74.1% overall. Conclusions: In this group of 81 patients with castrate resistant metastatic prostate cancer a previously defined model, which incorporates alk phos rise ≥100 in the preceding 3 months and/or Hb<11 is 74.1 % accurate in an independent group of patients. No patients with both alk phos rise>100 in the preceding 3 months, and Hb<11, responded to abiraterone. The model has potential in guiding treatment pathways on development of castrate resistance in prostate cancer, but needs to be tested in a greater number of patients.

scholarly journals Enzalutamide in Metastatic Prostate Cancer Before Chemotherapy

2021 ◽  
pp. 101-106
Author(s):  
Joseph Zabell
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Metastatic Prostate Cancer ◽  
Radiographic Progression ◽  
Progression Free Survival ◽  
Cytotoxic Chemotherapy ◽  
Free Survival ◽  
Prior Chemotherapy ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

This chapter summarizes the findings of the landmark PREVAIL trial conducted in men with castrate-resistant prostate cancer who had received prior chemotherapy comparing enzalutamide to placebo. It demonstrated improved overall survival, radiographic progression-free survival, and time to cytotoxic chemotherapy.

Abiraterone and Increased Survival in Metastatic Prostate Cancer

2021 ◽  
pp. 95-100
Author(s):  
Joseph Zabell
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Adverse Effects ◽  
Metastatic Prostate Cancer ◽  
Prior Chemotherapy ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

This chapter summarizes the findings of a landmark trial conducted in men with castrate-resistant prostate cancer who had received prior chemotherapy comparing abiraterone to placebo. It demonstrated improved progression-free and overall survival. It was relatively well tolerated, with most adverse effects related to mineralocorticoid excess.

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