scholarly journals Leptin antagonism inhibits prostate cancer xenograft growth and progression

2021 ◽  
Vol 28 (5) ◽  
pp. 353-375
Author(s):  
Lisa K Philp ◽  
Anja Rockstroh ◽  
Martin C Sadowski ◽  
Atefeh Taherian Fard ◽  
Melanie Lehman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Strategy ◽  
Leptin Receptor ◽  
Androgen Deprivation ◽  
Multiple Cancer ◽  
Current Therapies ◽  
Tumour Vascularity ◽  
Inflammation Targeting ◽  
Castrate Resistant ◽  
Hormone Signalling

Hyperleptinaemia is a well-established therapeutic side effect of drugs inhibiting the androgen axis in prostate cancer (PCa), including main stay androgen deprivation therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark pathways, including growth, proliferation, migration, angiogenesis, metabolism and inflammation, targeting the leptin axis is therapeutically appealing, especially in advanced PCa where current therapies fail to be curative. In this study, we uncover leptin as a novel universal target in PCa and are the first to highlight increased intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patients' tumours exposed to androgen deprivation, as is observed in patients' tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal the world-first preclinical evidence that demonstrates marked efficacy of targeted leptin-signalling blockade, using Allo-aca, a potent, specific, and safe LEPR peptide antagonist. Allo-aca-suppressed tumour growth and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour vascularity and altered pathways of apoptosis, transcription/translation, and energetics in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We highlight LEPR blockade in combination with androgen axis inhibition represents a promising new therapeutic strategy vital in advanced PCa treatment.

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).

Potential role of rituximab in metastatic castrate-resistant prostate cancer

2018 ◽  
Vol 25 (6) ◽  
pp. 1509-1511 ◽  
Author(s):  
Poorva Bindal ◽  
Sharif AA Jalil ◽  
Lisa M Holle ◽  
Jessica M Clement
Keyword(s):  
Prostate Cancer ◽  
B Cell ◽  
Disease Progression ◽  
Androgen Deprivation ◽  
Cell Infiltration ◽  
Prostate Cells ◽  
Develop Disease Progression ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Nearly all men with prostate cancer who are treated with androgen deprivation therapy develop disease progression. There is considerable evidence to suggest that CXCL 13 released by tumor cells leads to B-cell infiltration into the prostate cells. This B-cell infiltration has been postulated to play a role in development of disease progression following androgen-deprivation therapies. We present a case of a patient who achieved remission of metastatic castrate-resistant prostate cancer after receiving rituximab and bendamustine for the treatment of follicular lymphoma. The findings in this report suggest that further investigation is warranted for utilizing B-cell targeted therapy in delaying progression of castrate-resistant prostate cancer.

scholarly journals Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2426
Author(s):  
Stephanie Gleicher ◽  
Baylee A. Porter ◽  
Disharee Nath ◽  
Guanqun Li ◽  
Rakesh Khanna ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Androgen Deprivation Therapy ◽  
Metastatic Disease ◽  
Biochemical Recurrence ◽  
Current Therapies ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Novel Target ◽  
Resistant State

Nearly one third of men will incur biochemical recurrence after treatment for localized prostate cancer. Androgen deprivation therapy (ADT) is the therapeutic mainstay; however, some patients will transition to a castrate resistant state (castrate resistant prostate cancer, CRPC). Subjects with CRPC may develop symptomatic metastatic disease (mCRPC) and incur mortality several years later. Prior to metastatic disease, however, men acquire non-metastatic CRPC (nmCRPC) which lends the unique opportunity for intervention to delay disease progression and symptoms. This review addresses current therapies for nmCRPC, as well as novel therapeutics and pathway strategies targeting men with nmCRPC.

scholarly journals Benefits of intermittent/continuous androgen deprivation in patients with advanced prostate cancer

2016 ◽  
Vol 89 (3) ◽  
pp. 419-422 ◽  
Author(s):  
Horia Muresanu
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Survival Rates ◽  
Androgen Deprivation ◽  
Gnrh Analogue ◽  
Serious Adverse Events ◽  
Androgen Independence ◽  
Deprivation Group ◽  
Long Time ◽  
Castrate Resistant

Background and aims: Huggins described in 1941 the effect of castration on prostate cancer. Gonadotropin-releasing hormone (GNRH) analogue were introduced in 1985. Complete androgen blocade (association of GNRH analogue with antiandrogen) was introduced by Fernand Labrie to achieve supression of suprarenalian testosterone. Long time androgen deprivation lead to androgen independence of prostate cancer cell.Our principal aim was to demonstrate longer survival rates on prostate cancer patients with intermittent androgen deprivation.Methods: 82 patients were enrolled at the Urology Deparment of West University „Vasile Goldiș” Arad in two groups with continous and intermittent androgen deprivation.Treatment efficiency was assesed by the level of testosterone and PSA.Adverse events (AE) and serious adverse events were reported  according to Common Terminology Cryteria of Adverse Events (CTCAE) of the National Cancer Institute  (NCI).Results:Evolution towards castrate resistant prostate cancer: 12.5% from the intermittent androgen deprivation group and 23.8% from the continues androgen deprivation groupMortality rate: 15% of patients from the intermittent androgen deprivation group; 19% of patients from the continue androgen deprivation group Conclusions:1. Better quality of life (Qo)l in periods without treatment due to testosteron recovery; 2. Less AE’s and methabolic syndrom (MS) related complications; 3. Better survival and longer time of disease control and 4. Cost reduction

SM88/SMK non-hormonal therapy in recurrent or untreated prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16540-e16540
Author(s):  
Steve Hoffman ◽  
John Rothman ◽  
Giuseppe Del Priore ◽  
Jeanetta Stega
Keyword(s):  
Prostate Cancer ◽  
Retrospective Chart Review ◽  
Androgen Deprivation ◽  
Cancer Therapies ◽  
Patients With Cancer ◽  
Resistant Disease ◽  
Significant Toxicity ◽  
Days Of Therapy ◽  
Hispanic Patients ◽  
Castrate Resistant

e16540 Background: Prostate cancer (PC) has a poor prognosis. Androgen deprivation therapy is effective but has unacceptable short and long term side effects. SM88 (modulators of mTOR, mitochondrial stress, CYP3a4 and tyrosine isomers) is a novel combination of anti-cancer therapies with previously reported favorable results yet low toxicity in a heterogeneous group of 30 patients with cancer. We now report on a PC cohort treated with SM88. Methods: Retrospective chart review. Results: Between 2012 and 2014, 6 men with PC were treated with SM88, administered 5 days/week over a 6-week treatment cycle. SM88 consisted of daily oral and subcutaneous injection of the components. The average age was 54 years (range 32-66). Five (83.3%) were Caucasian, 1 (16.7%) was Hispanic. patients with prostate cancer were treated with SM88 daily, Monday-Friday, for between 6 to 31 wks (median 11). Four patients had castrate resistant disease, two declined ADT. One had failed prior chemotherapy (see Table). All subjects were not receiving other therapy. One subject died of disease complications approximately 3 months after starting treatment but only received approximately 20 days of therapy over a 6 week cycle. Three patients had PSA nadir responses of >90% reduction over pretreatment peak levels (see table). Two others had radiographic SD for between 10-14 wks. There were no significant toxicity except cutaneous hyperpigmentation. The duration of responses ranged from 10-114 weeks. Best overall responses included 2 patients with complete biochemical response. Four subjects improved their ECOG score during treatment and 2 had no change. Conclusions: SM-88 appears to be well tolerated and to have anti-tumor activity in prostate cancer without androgen deprivation toxicity. Additional confirmatory prospective studies in prostate are ongoing and planned in other cancers. [Table: see text]

Multi-parametric liquid biopsy analysis of circulating tumor cells (CTCs), cell-free DNA (cfDNA), and cell-free RNA (cfRNA) in metastatic castrate resistant prostate cancer (mCRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 274-274 ◽  
Author(s):  
Emmanuelle Hodara ◽  
Daniel Zainfeld ◽  
Gareth Morrison ◽  
Alexander Cunha ◽  
Yucheng Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Liquid Biopsy ◽  
Copy Number ◽  
Cell Capture ◽  
Multiple Cancer ◽  
Liquid Biopsies ◽  
Low Pass ◽  
Number Variation ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

274 Background: Molecular profiling of prostate cancer using liquid biopsies such as CTC capture and cell-free nucleic acid analysis yield informative yet distinct datasets. Additional insights may be gained by simultaneously interrogating multiple liquid biopsy components to construct a more comprehensive molecular disease profile. We have conducted an initial proof of principle study aimed at piloting this multi-parametric approach. Methods: Blood was drawn under an IRB-approved protocol from 20 mCRPC patients. Samples were analyzed simultaneously for the following: CTC enumeration and single CTC and matched white blood cell capture for whole genome amplification and low-pass copy number variation; CTC DNA and matched cfDNA for somatic single nucleotide variant analysis; plasma cfRNA extraction and qRT-PCR for AR, AR-V7, and PCA3. When available, liquid biopsies were compared with matched tumor profiles. Results: Fifteen of 20 patients (75%) had detectable CTCs by CellSearch (range: 1-692/7.5mL, median: 16.5/7.5mL). Thirteen of 20 patients (65%) had detectable SSNVs in CTC DNA and/or matched cfDNA, including mutations in TP53, PIK3CA, HRAS, and EGFR. Matched CTC DNA and cfDNA demonstrated both shared and distinct SSNVs. Copy number analysis of single CTCs was performed in 2 patients, and both had CNVs in multiple cancer relevant genes. A majority of CNVs were present in matched solid tumor profiles, but some were exclusive to the liquid biopsies. Plasma PCA3 and AR transcripts were detected in 18/20 (90%) and AR-V7 in 4/20 (20%) cfRNA samples. Unique SSNVs were detected at second time points at disease progression (more are being collected). Conclusions: In this pilot cohort, simultaneous multi-parametric profiling was feasible for CTC DNA mutations and CNVs, and matched plasma cfDNA mutations and cfRNA gene expression. These disease-specific molecular profiles were often concordant with tumor tissues but also contained new, potentially actionable alterations unique to CTC DNA or cfDNA. Expanded studies will build upon this approach to optimally leverage liquid biopsies for molecularly directed patient management.

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