Dr. Weeks’ Comment: Medical doctors need to focus on what is known in order to be able to provide the standard of care, but in addition, some doctors keep a weather eye open for what paradigms are shifting so as to provide “tomorrow’s medicine today”. We all know that men in the prime of life when their testosterone levels are high rarely get prostate cancer. The risk of prostate cancer increases when men age and their testosterone output is reduced and their rate of conversion of testosterone to carcinogenic estrogen raises. We were all taught that men with prostate cancer must have testosterone (androgen) deprivation therapy which blocks the physiologic effect of testosterone because in 1941 Dr. Huggins claimed (from a case study of 4 men) that “testosterone is like fuel on the fire” for men with prostate cancer. We now know that that opinion is not entirely accurate and that there may be a role for testosterone in men with prostate cancer.
Testosterone Therapy in Men with Biochemical Recurrence and Metastatic Prostate Cancer:
Initial Observations
Abraham Morgentaler,1,*,i Alejandro Abello,1,iiand Glenn Bubley2
Androgens: Clinical Research and Therapeutics
Volume 2.1, 2021 DOI: 10.1089/andro.2021.0001 Accepted April 26, 2021
Abstract
Introduction: Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET).
Methods: We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed.
Results: Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. Median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture.
Conclusions: These initial observations indicate testosterone therapy (TTh) was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.
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Effect of bipolar androgen therapy for asymptomatic
men with castration-resistant prostate cancer: Results
from a pilot clinical study
Michael T. Schweizer,*†Emmanuel S. Antonarakis, Hao Wang, A. Seun Ajiboye, Avery Spitz,
Haiyi Cao, Jun Luo, Michael C. Haffner, Srinivasan Yegnasubramanian, Michael A. Carducci,
Mario A. Eisenberger, John T. Isaacs, Samuel R. Denmeade†
www.ScienceTranslationalMedicine.org 7 January 2015 Vol 7 Issue 269 269ra2 1
INTRO: Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment. However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death. Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy. Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT). BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs. BAT shows promise as treatment for CRPC and should be further evaluated in larger trials.
In summary, this study provides preliminary evidence that asymptomatic men with advanced CRPC can be safely treated with BAT to achieve rapid cycling between supraphysiologic and near-castrate serum testosterone levels to produce an antitumor effect.Although PSA flares were observed in some men, there were no symptomatic flare reactions with BAT administration, and BAT produced objective radiographic responses in 50% of patients. Although these results are encouraging, it should be emphasized that the results of this pilot study need confirmation before adopting BAT into a clinical setting, and additional clinical trials are essential to determine whether this treatment approach is safe and effective. Because PSA is an androgen-stimulated gene product, its use as a marker of disease response to BAT is inherently problematic. Thus, future studies should use radiographic or survival endpoints. Finally, the results from this pilot study support future work toward establishing BAT as an effective therapy that can improve survival, overcome resistance to androgen ablative therapies, and meaningfully improve quality of life, functional activity, and sexual function in men with CRPC.
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Eur Urol. 2016 May;69(5):894-903.
doi: 10.1016/j.eururo.2015.12.005. Epub 2015 Dec 21.
Testosterone Therapy in Men With Prostate Cancer
Alan L Kaplan 1, Jim C Hu 2, Abraham Morgentaler 3, John P Mulhall 4, Claude C Schulman 5, Francesco Montorsi 6
Abstract
Context: The use of testosterone therapy in men with prostate cancer was previously contraindicated, although recent data challenge this axiom. Over the past 2 decades, there has been a dramatic paradigm shift in beliefs, attitude, and treatment of testosterone deficiency in men with prostate cancer.
Objective: To summarize and analyze current literature regarding the effect of testosterone replacement in men with prostate cancer.
Evidence synthesis: The historical notion that increasing testosterone was responsible for prostate cancer growth was based on elegant yet limited studies from the 1940s and anecdotal case reports. Current evidence reveals that high endogenous androgen levels do not increase the risk of a prostate cancer diagnosis.Similarly, testosterone therapy in men with testosterone deficiency does not appear to increase prostate cancer riskor the likelihood of a more aggressive disease at prostate cancer diagnosis. Androgen receptor saturation (the saturation model) appears to account for this phenomenon. Men who received testosterone therapy after treatment for localized prostate cancer do not appear to suffer higher rates of recurrence or worse outcomes; although studies to date are limited. Early reports of men on active surveillance/watchful waiting treated with testosterone have not identified adverse progression events.
Conclusions: An improved understanding of the negative effects of testosterone deficiency on health and health-related quality of life-and the ability of testosterone therapy to mitigate these effects-has triggered a re-evaluation of the role testosterone plays in prostate cancer. An important paradigm shift has occurred within the field, in which testosterone therapy may now be regarded as a viable option for selected men with prostate cancer suffering from testosterone deficiency.
Patient summary: In this article, we review and summarize the existing literature surrounding the use of testosterone therapy in men with prostate cancer. Historically, testosterone was contraindicated in men with a history of prostate cancer. We show that this contraindication is unfounded and, with careful monitoring, its use is safe in that regard.
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Lancet Oncol. 2018 Jan;19(1):76-86.
doi: 10.1016/S1470-2045(17)30906-3. Epub 2017 Dec 14.
Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study
Benjamin A Teply 1, Hao Wang 2, Brandon Luber 2, Rana Sullivan 2, Irina Rifkind 2, Ashley Bruns 2, Avery Spitz 2, Morgan DeCarli 2, Victoria Sinibaldi 2, Caroline F Pratz 2, Changxue Lu 3, John L Silberstein 3, Jun Luo 3, Michael T Schweizer 4, Charles G Drake 5, Michael A Carducci 2, Channing J Paller 2, Emmanuel S Antonarakis 2, Mario A Eisenberger 2, Samuel R Denmeade 6
Abstract
Background: Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide.
Methods: We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0-2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114.
Findings: Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15-49; p<0·0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33-71; p<0·0001) achieved a PSA50 response. During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment.
Interpretation: BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximize therapeutic benefit to patients.
Evans CP.Lancet Oncol. 2018 Jan;19(1):8-10. doi: 10.1016/S1470-2045(17)30907-5. Epub 2017 Dec 14.PMID: 29248235 No abstract available.
Stone L.Nat Rev Urol. 2018 Feb;15(2):67. doi: 10.1038/nrurol.2017.223. Epub 2018 Jan 3.PMID: 29297892 No abstract available.
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Eur Urol. 2021 May;79(5):692-699.
doi: 10.1016/j.eururo.2020.06.042. Epub 2020 Jul 2.
A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts
Mark C Markowski 1, Hao Wang 2, Rana Sullivan 3, Irina Rifkind 3, Victoria Sinibaldi 3, Michael T Schweizer 4, Benjamin A Teply 5, Nduku Ngomba 3, Wei Fu 2, Michael A Carducci 3, Channing J Paller 3, Catherine H Marshall 3, Mario A Eisenberger 3, Jun Luo 6, Emmanuel S Antonarakis 3, Samuel R Denmeade 3
Abstract
Background: Cyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents.
Objective: To evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT.
Design, setting, and participants: RESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy.
Results and limitations: No statistically significant difference in PSA50 response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA50 responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005).
Conclusions: BAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone.
Patient summary: BAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7-positive patients.
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Reversing the effects of androgen-deprivation therapy in men with metastatic castration-resistant prostate cancer
BJU InternationalVolume 128, Issue 3, September 2021, Pages 366-373
Marshall, C.H.,Denmeade, S.R.,
Objective: To investigate whether bipolar androgen therapy (BAT), involving rapid cyclic administration of high-dose testosterone, as a novel treatment for metastatic castration-resistant prostate cancer (mCRPC) promotes improvements in body composition and associated improvements in lipid profiles and quality of life.
Patients and Methods: Men from two completed trials with computed tomography imaging at baseline and after three cycles of BAT were included. Cross-sectional areas of psoas muscle, visceral and subcutaneous fat were measured at the L3 vertebral level. Functional Assessment of Chronic Illness Therapy – Fatigue questionnaire and 36-item short-form health survey were used to assess quality of life. Results: The 60 included patients lost a mean (sd) of 7.8 (8.2)% of subcutaneous fat, 9.8 (18.2)% of visceral fat, and gained 12.2 (6.7)% muscle mass. Changes in subcutaneous and visceral fat were positively correlated with each other (Spearman’s correlation coefficient 0.58, 95% confidence interval 0.35–0.71) independent of the effects of age, body mass index, and duration of androgen-deprivation therapy. Energy, physical function, and measures of limitations due to physical health were all significantly improved at 3 months. The improvements in body composition were not correlated with decreases in lipid levels or observed improvements in quality of life.
Conclusions: In the present study, BAT was associated with significant improvements in body composition, lipid parameters, and quality of life. This has promising implications for the long-term health of men with mCRPC.
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Eur Urol. 2017 Mar;71(3):499.
doi: 10.1016/j.eururo.2016.09.020. Epub 2016 Sep 29.
Extreme Response to High-dose Testosterone in BRCA2- and ATM-mutated Prostate Cancer
Benjamin A Teply 1, Sushant Kachhap 1, Mario A Eisenberger 1, Samuel R Denmeade 2
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Eur J Cancer. 2021 Feb;144:302-309.
doi: 10.1016/j.ejca.2020.11.043. Epub 2020 Dec 29.
Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy
Laura A Sena 1, Hao Wang 1, Su J Lim ScM 1, Irina Rifkind 1, Nduku Ngomba 1, John T Isaacs 1, Jun Luo 1, Caroline Pratz 1, Victoria Sinibaldi 1, Michael A Carducci 1, Channing J Paller 1, Mario A Eisenberger 1, Mark C Markowski 1, Emmanuel S Antonarakis 1, Samuel R Denmeade 2
Abstract
Background: Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC.
Patients and methods: In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA50 response rate to BAT treatment.
Results: After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4-32%) experienced a PSA50 response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9-15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73-100%) achieved a PSA50 response and 15 of 18 patients (83%; 95% CI: 59-96) achieved a PSA90 response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52-96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months.
Conclusion: As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor-targeted therapy.
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Eur Urol. 2017 Sep;72(3):323-325.
doi: 10.1016/j.eururo.2017.03.022. Epub 2017 Mar 29.
Bipolar Androgen Therapy: A Paradoxical Approach for the Treatment of Castration-resistant Prostate Cancer
Michael T Schweizer 1, Emmanuel S Antonarakis 2, Samuel R Denmeade 3
Abstract
Bipolar androgen therapy (BAT) is a paradoxical treatment for castrate-resistant prostate cancer whereby testosterone levels are rapidly alternated between supraphysiologic and near-castrate concentrations.Initial studies demonstrated that BAT is safe and produces clinical responses. A trial comparing enzalutamide against BAT is ongoing.
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Endocr Relat Cancer. 2006 Sep;13(3):653-66.
doi: 10.1677/erc.1.00797.
Combinatorial androgen receptor targeted therapy for prostate cancer
P Singh 1, A Uzgare, I Litvinov, S R Denmeade, J T Isaacs
Abstract
Prostatic carcinogenesis is associated with changes in the androgen receptor (AR) axis converting it from a paracrine dependence upon stromal signaling to an autocrine-initiated signaling for proliferation and survival of prostatic cancer cells. This malignant conversion is due to gain of function changes in which the AR activates novel genomic (i.e. transcriptional) and non-genomic signaling pathways,which are not present in normal prostate epithelial cells.During further progression, additional molecular changes occur which allow these unique malignancy-dependent AR signaling pathways to be activated even in the low androgen ligand environment present following androgen ablation therapy. These signaling pathways are the result of partnering the AR with a series of other genomic (e.g. transcriptional co-activators) or non-genomic (e.g. steroid receptor co-activator (Src) kinase) signaling molecules. Thus, a combinatorial androgen receptor targeted therapy (termed CART therapy) inhibiting several points in the AR signaling cascade is needed to prevent the approximately 30,000 US males per year dying subsequent to failure of standard androgen ablation therapy. To develop such CART therapy, a series of agents targeted at specific points in the AR cascade should be used in combination with standard androgen ablative therapy to define the fewest number of agents needed to produce the maximal therapeutic anti-prostate cancer effect.
As an initial approach for developing such CART therapy, a variety of new agents could be combined with luteinizing hormone-releasing hormone analogs. These include: (1) 5alpha-reductase inhibitors to inhibit the conversion of testosterone to the more potent androgen, dihydrotestosterone; (2) geldanamycin analogs to downregulate AR protein in prostate cancer cells, (3) ‘bulky’ steroid analogs, which can bind to AR and prevent its partnering with other co-activators/signaling molecules, and (4) small molecule kinase inhibitors to inhibit MEK, which is activated as part of the malignant AR signaling cascade.
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Serial bipolar androgen therapy (sBAT) using cyclic supraphysiologic testosterone (STP) to treat metastatic castration-resistant prostate cancer (mCRPC)
John T. Isaacs1,2, W. Nathaniel Brennen1,2, Samuel R. Denmeade1,2
Annals of Translational Medicine Vol 7, Supplement 8 (December 2019): Annals of Translational Medicine / doi: 10.21037/atm.2019.10.32
During prostate carcinogenesis, molecular changes occur in prostate epithelial cells such that their Androgen Receptor (AR) protein expression increases significantly (i.e. >5 fold). This elevated AR expressionperverts AR-dependent transcriptional programming from a growth suppressor to an oncogenic stimulator of malignant growth (1–3). Due to this malignancy acquired addiction to AR transcriptional programming, androgen deprivation therapy (ADT), which lowers serum testosterone (T) from 600 to <100 ng/dL, not only inhibits prostate cancer cell proliferation, but also results in transcriptional reprogramming that induces cancer cell death (4). Unfortunately, metastatic prostate cancer patients eventually develop resistance to primary castration therapyin addition to secondary hormone-based therapies such as abiraterone and/or enzalutamide. The most common mechanism for the development of resistance is via an adaptive “auto-regulation” that increases AR protein expression by >30-fold (5). This increase results in sufficient AR accumulation in the nuclei of castration-resistant prostate cancer (CRPC) cells to induce by mass action the AR-dependent transcriptional programming needed to both inhibit their death and stimulate their proliferation despite castrate levels of androgen.
While this adaptive increase in AR provides a growth advantage under ADT conditions, it creates the potential for an “induced synthetic lethality” in these malignant cells. The basis for this induced synthetic lethality is derived from the fact that the half-life of the AR protein is more than doubled when fully occupied by androgen (5). Thus, when high AR-expressing CRPC cells are cycled from low (i.e., <100 ng/dL) to supraphysiologic (>700 ng/dL) androgen (SPT), the resultant fully ligand-occupied AR protein is stabilized, driving its accumulation in the nucleus to such a high level that it now “paradoxically” suppresses proliferation and induces cell death (5–10). Several complementary mechanisms for the paradoxical effect of SPT have been described. Using both in vitro cell lines and in vivo xenograft models Isaacs et al. demonstrated that AR is a DNA licensing factor that plays a critical role in DNA replication and must be degraded as a cell goes through the cell cycle (11). These studies also documented that treatment with SPT saturates ligand binding to the AR, maximizing the amount of ligand-bound AR in the nucleus and stabilizing it against degradation, thus inhibiting DNA relicensing,which results in cell death in the subsequent cycle (12,13). In independent studies, Haffner et al. documented that treatment of CRPC cells with SPT increases AR nuclear binding to DNA, generating transient double-strand DNA breaks in these cells through the recruitment of AR and topoisomerase IIβ to androgen response elements leading to death of these cells (14,15). An additional rationale for the use of SPT is the observation that there are differences in the AR transcriptome when CRPC cell lines with high levels of AR are exposed to either high or low androgen concentrations (16,17). Under high androgen conditions, AR represses several genes, including AR itself in addition to those involved in androgen synthesis, DNA synthesis, cell proliferation and survival (e.g., c-MYC, BCL2, NFκB). Therefore, SPT can lead castration-resistant cells to transition from a more oncogenic transcriptome associated with castrate T levels to a high androgen transcriptome that does not support cancer proliferation and survival(16,17).
Indeed, the recent publication of Lam et al. documents that treatment with SPT durably suppresses the in vivo growth of 4 out of 13 AR-expressing patient-derived CRPC xenografts (PDXs) due to a multifaceted growth suppression and impaired DNA damage response transcriptional program (18). In the Lam et al. study, CRPC PDXs were initially established in castrated hosts and then supplemented with exogenous testosterone to rapidly raise and maintain the serum testosterone from <100 ng/dL to a supraphysiologic value of >700 ng/dL (18). In contrast to the SPT maintenance approach of Lam et al. to induce lethality in CRPC cells, our group previously proposed that additional therapeutic advantage can be gained by cycling between short periods (i.e., 2 weeks) of SPT back to a castrate level of T (5,19). This cycling optimally inhibits growth and induces cell death in high AR expressing CRPC cells; a strategy we termed serial bipolar androgen therapy (sBAT). The rationale for this sBAT approach is that during such rapid cycling, any subset of CRPC cells that “auto-regulate” to decrease transcription of AR fast enough to lower AR protein levels, thus preventing both transcriptional reprogramming to a growth suppressive transcriptome and not inhibiting DNA replication licensing or fragmentation, can survive such SPT exposure. However, if these surviving now low AR-expressing cells are subsequently rapidly cycled back to castrate T, they must rapidly re-upregulate AR transcription to elevate AR protein to a high enough level to maintain the oncogenic transcriptome needed to survive and grow in the now low androgen environment. Such AR auto-upregulation, however, re-sensitizes them to another round of SPT. By serially cycling systemic androgen rapidly between the bipolar extremes of SPT and castrate levels, CRPC cells are placed in a highly stressful and energy demanding compromised state of constant transcriptional reprogramming, which in preclinical patient-derived human CRPC xenograft models inhibits their survival and growth. See Figure 1 for an example of such a therapeutic response.
Based on this rationale, sBAT has been translated clinically in metastatic CRPC patients progressing on second line hormone therapies (i.e., abiraterone and/or enzalutamide) through intramuscular administration of 400 mg of T cypionate every 28 days to rapidly raise serum T to supraphysiologic levels >1,500 ng/dL by 2 days post-injection with a decline to near castrate level (~100 ng/dL) by 28 days post-injection,
Overall, sBAT has produced minimal side effects and shown clinical responses in ~25% of patients (20–22). These positive results raise the issue of how to increase both the frequency and extent of clinical benefit resulting from the sBAT regimen. The fundamental therapeutic basis of sBAT is the mandatory requirement for rapid, adaptive auto-regulation of AR and its transcriptome by CRPC cells during the rapid extreme changes in androgen concentrations. Therefore, we are presently testing whether the therapeutic benefit of sBAT can be increased by combining it with appropriately timed transcriptional inhibitors targeting different, but complimentary epigenetic regulators to disrupt the adaptive transcriptional reprogramming by CRPC cells needed for their survival and proliferation during rapid extreme changes in androgen level.