ADT, Androgen Deprivation Therapy, “Hormone Therapy” and Zolodronic Acid therapy (bisphosphonate) are considered to be the “gold standard” of care.
Are they worth the risk?
ADT: Castrate-Resistant Prostate Cancer (CRPC) is inevitable
“ADT is commonly employed in the treatment of advanced prostate cancer. But androgen deprivation therapy is not curative [2], so the lethal CRPC is inevitable.”
“… the mechanisms by which tumors acquire androgen independence remain unclear and need to be addressed before effective treatment strategies can be developed.”
\GRP78 ADT CRPC metabolism 2013.pdf
Somatostatin Derivative (smsDX) Targets Cellular Metabolism in
Prostate Cancer Cells after Androgen Deprivation Therapy
Lei Yan1., Zhaoquan Xing1., Zhaoxin Guo1, Zhiqing Fang1, Wei Jiao1, Xiaoyu Guo2, Zhonghua Xu1*,
Zhenghui Fang3, Anders Holmberg4, Sten Nilsson4, Zhaoxu Liu1,2,4*
1 Department of Urology, Qilu Hospital, Shandong University, Jinan, China, 2 Aging and Health Center,
School of Nursing, Shandong University, Jinan, China, 3 Department of Obstetrics and Gynecology, Jinan Central Hospital,
Shandong University, Jinan, China, 4 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
Published February 7, 2013
Zolodronic Acid, “the Gold Standard (and only approved bisphonate)”
“Zoledronic acid has an acceptable safety profile and tolerability, and has been effective at significantly decreasing the incidence, delaying the onset, and reducing the overall risk of experiencing an SRE (skeletal-related events) compared to placebo. It is the only bisphosphonate currently approved for the prevention and treatment of skeletal complications in patients with bone metastases due to all solid tumors.”
“Androgen deprivation therapy, which is commonly employed therapeutically in advanced prostate cancer, increases bone loss and subsequent fracture risk (Daniell et al 1997).”
“The National Comprehensive Cancer Network Guidelines on Prostate Cancer state that early bisphosphonate therapy of all men with prostate cancer treated with androgen deprivation therapy may prevent androgen-deprivation and/or bone metastasis related morbidity and improve quality of life (NCCN guidelines).”
“Zoledronic acid is the gold standard for the medical management of metastatic bone disease. “
Zoledronic acid in the management of metastatic bone disease
Thomas J Polascik and Vladimir Mouraviev
Duke Prostate Center and Division of Urologic Surgery, Duke University Medical Center
Therapeutics and Clinical Risk Management, 2008
\ZOL metastasis bone PC 2008.pdf
ZOL “…no benefit in time to first SRE, skeletal-related event”
“The median time to first SRE (skeletal-related event) was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group…”
Randomized Controlled Trial of Early Zoledronic Acid in Men With Castration-Sensitive
Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance)
Smith M R, et al., Massachusetts General Hospital Cancer Center, Duke University Medical Center,
University of California San Francisco, University of Chicago, Nevada Cancer Research Foundation,
University of Omaha, Ohio State University, Memorial Sloan-Kettering Cancer Center
Journal of Cancer Oncology, 2014
\ZOL trial bone mets PC 2014.pdf
Zoledronic Acid “…does not prevent metastasis, no survival benefit”
“Zoledronic acid (Zometa, Novartis) is no better at preventing bone metastasis in high-risk prostate cancer patients than standard treatment, results from the Zometa European Study (ZEUS) show.”
“There were no differences in the incidence of bone metastasis. The primary end point was not achieved so it’s a negative trial,” said principal investigator Manfred Wirth, MD, from the University Clinic of the Technical University of Dresden in Germany. There was also no survival benefit associated with zoledronic acid, he noted.”
“The rates of bone metastasis were similar in the zoledronic acid and control groups (13.7% vs 13.0%; P = 0.721). “There was absolutely no difference between the groups,” said Dr. Wirth.
“There was also no difference in overall survival between the 2 groups (P = 0.717). In addition, there was no significant difference between the death rate from prostate cancer and the rate from other causes, he noted.”
Zoledronic Acid Fails to Halt Metastasis in Prostate Cancer
Kate Johnson, Medscape Medical News, 2013
\ZOL fails halt mets 2013.pdf
Zoledronic Acid – “…resistance and more aggressive and invasive phenotype”
“Thus, for the first time, we demonstrate that the p38- MAPK pathway can be activated under continuous extensive exposure to ZOL (Zoledronic acid) in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.”
“Despite the importance of ZOL in the clinical management of cancer, few studies have reported the molecular mechanisms underlying the development of ZOL resistance in cancer cells.[11–13]”
“In our study, we have selected and characterised for the first time a ZOL-resistant PCa cell line. Notably, in addition to specific resistance to the antiproliferative and pro-apoptotic effects of ZOL, this cell line acquired a very aggressive phenotype that is characterised by resistance to anoikis, increased invasive capability and epithelial to mesenchymal transition (EMT).”
\Zoledronic acid resistance p38 MAPK 2013.pdf
Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive
phenotype are mediated by p38-MAP kinase activation in prostate cancer cells
MR Milone1,4, B Pucci1,4, F Bruzzese2, C Carbone2,5, G Piro1,5, S Costantini1, F Capone1, A Leone2, E Di Gennaro2,
M Caraglia3 and A Budillon*,1,2
1Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy;
2Experimental Pharmacology Unit, Department of Research, IRCCS-Istituto
Nazionale Tumori G Pascale, Naples, Italy and 3Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
*Corresponding author: A Budillon, Experimental Pharmacology Unit, National Cancer Institute of Naples,
IRCCS-Istituto Nazionale Tumori G Pascale, Via M Semmola,Naples 80131, Italy.
5Present address: University of Verona, Verona, Italy.
Citation: Cell Death and Disease (2013) 4, e641; doi:10.1038/cddis.2013.165
& 2013 Macmillan Publishers Limited All rights reserved 2041-4889/13
ADT “…disease progression inevitable”
“Although advanced prostate cancer is generally sensitive to initial androgen deprivation therapy (ADT), responses are in most cases not durable and disease progression is inevitable.”
\therapeutics adv PC 2014.pdf (01-30-2015)
Sequential use of novel therapeutics in advanced prostate
cancer following docetaxel chemotherapy
Aurelius Omlin, Carmel Pezaro and Silke Gillessen Sommer
Aurelius Omlin, MD, Kantonsspital St Gallen, Abteilung fuer Medizinische Onkologie, Rorschacherstrasse 95,
CH-9007 St Gallen, Switzerland
aurelius.omlin@kssg.ch Carmel Pezaro, MD Monash University Eastern Health Clinical School, Australia
Silke Gillessen Sommer, MD Kantonsspital St Gallen, St Gallen, Switzerland
Ther Adv Urol
2014, Vol 6(1) 3–14
DOI: 10.1177/ 1756287213509677
ADT “…with anti-androgens promotes Prostate Cancer metastasis”
“Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion.”
“Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway.”
“Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 (nutritional metabolite) alone or a combinational therapy …”
“ASC-J9, but not Casodex and MDV3100, suppressed both macrophage infiltration and PCa metastasis in the in vivo mouse models.”
Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads toopposite
effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling
Lin T H, Izumi K, Lee S O, Lin W-J, Yeh S, Chang C
George Whipple Lab for Cancer Research, University of Rochester Medical Center, Department of Urology, Department
of Radiation Oncology, The Wilmont Cancer Center, Sex Hormone Research Center, China Medical University
Journal Cell Death and Disease, 2013
http://www.ncbi.nlm.nih.gov/pubmed/23928703
\ASC-J9 vs casodex MDV3100 CRPC 2013.pdf
ADT involved in several pathways which promote metastasis
“Recent studies suggested that several cell types in the prostate tumor microenvironment (TME) might contribute to the prostate cancer (PCa) progression [1–11]. For example, infiltrating macrophages might promote PCa metastasis via modulation of CCL2/CCR2- STAT3 signaling [7–9] and recruited endothelial cells might also be able to promote PCa metastasis via modulation of IL6 signaling [10]. Our previous study demonstrated that infiltrating bone marrow derived mesenchymal stem cells (BM-MSCs) might be able to enhance PCa cell invasion via altering the cancer stem cell differentiation. The mechanism dissection revealed that this regulation involves the modulation of CCL5 and AR signaling [11]. The CCL5 secreted from BM-MSCs can increase the cancer stem cell and EMT markers, such as the CD133, ZEB-1 and CXCR4. The findings that AR in individual cells within the TME might play differential roles (positive vs negative roles) could further complicate the androgen/AR signaling in PCa progression [7–13] and raised special questions about the current androgen deprivation therapy (ADT), which systematically suppresses/reduces androgen from binding to AR in every cell, to suppress the progression of PCa, a disease that has become the most prevalent cancer among males in United States with the 2nd highest mortality rate. [8, 9, 14, 15].”
\BM-MSC CCL5 HIF1a PC mets 2013.pdf
ADT – “infiltrating T-cells…”
“Here, we found PCa cells have a better capacity to recruit more CD4(+) T cells than the surrounding normal prostate cells via secreting more chemokinesCXCL9. The consequences of more recruited CD4(+) T cells to PCa might then lead to enhance PCa cell invasion. Mechanism dissection revealed that infiltrating CD4(+) T cells might function through the modulation of FGF11→miRNA-541 signals to suppress PCa androgen receptor (AR) signals. The suppressed AR signals might then alter the MMP9 signals to promote the PCa cell invasion. Importantly, suppressed AR signals via AR-siRNA or anti-androgen Enzalutamidein PCa cells also enhanced the recruitment of T cells and the consequences of this positive feed back regulation could then enhance the PCa cell invasion.”
\infiltrating T-cells PC mets 2015.pdf
ADT – “infiltrating mast cells…”
“Early studies indicated that selective inflammatory immune cells in the prostate tumor microenvironment might be able to influence prostate cancer (PCa) progression. Here we found treating PCa cells with androgen deprivation therapy (ADT) results in the recruitment of more mast cells, which might then increase PCa cell invasion via down-regulation of AR signals in 4 different PCa cell lines.”
“The consequences of suppressing AR may then increase PCa cell invasion via increased MMP9 expression and/or increased stem/progenitor cell population.”
“Here we found ADT treatment of PCa resulted in increased cell invasion via increased numbers of recruited mast cells – PCa AR-MMP9 signals and alteration of the AR-induced stem/progenitor cell population.”
\infiltrating mast cells PC invasion 2015.pdf
ADT Adverse Effects: additional drugs the solution?
“Adverse effects of ADT include decreases in bone mineral density; metabolic changes such as weight gain, decreased muscle mass, and increased insulin resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced testicle size; anemia; and fatigue. Several observational studies suggest an increased risk of diabetes and cardiovascular events, although most published studies report that ADT is not linked to greater cardiovascular mortality. Randomized trials have found value in treatments for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia (tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and hot flashes (venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin).”