Abiraterone Acetate,A Novel Adrenal Inhibitor in Metastatic Castration-Resistant Prostate Cancer

The androgen receptor remains the key player in patients with castration-resistant prostate cancer (CRPC). Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities. Abiraterone acetate, a pregnenolone analog, is a small molecule that irreversibly inhibits CYP17, a rate-limiting enzyme in androgen biosynthesis. Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC. Recently, a randomized phase 3 trial evaluating abiraterone acetate in docetaxel-refractory CRPC patients demonstrated a survival improvement over placebo-treated patients (14.8 vs 10.9 months; HR 0.646; P < 0.0001). A similar trial in the pre-chemotherapy setting has completed accrual and is undergoing analysis. Here we review the rationale and clinical development of abiraterone acetate in men with CRPC.     

Activity of Cabazitaxel After Docetaxel and Abiraterone Acetate Therapy in Patients With Castration-Resistant Prostate Cancer

BackgroundCabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC.Patients and MethodsOne hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods.ResultsTwenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69).ConclusionA limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.     

Use of Prednisone With Abiraterone Acetate in Metastatic Castration‐Resistant Prostate Cancer

Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone that blocks androgen biosynthesis, is approved for treatment of patients with metastatic castration‐resistant prostate cancer (mCRPC) in combination with prednisone or prednisolone 5 mg twice daily. This review evaluates the basis for the effects of prednisone on mineralocorticoid‐related adverse events that arise because of CYP17A1 inhibition with abiraterone. Coadministration with the recommended dose of glucocorticoid compensates for abiraterone‐induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone. Consequently, 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate, analogous to use of glucocorticoid replacement therapy for certain endocrine disorders. We searched PubMed to identify safety concerns regarding glucocorticoid use, placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer. In general, glucocorticoid‐related adverse events, including bone loss, immunosuppression, hyperglycemia, mood and cognitive alterations, and myopathy, appear dose related and tend to occur at doses and/or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC. Although glucocorticoids are often used to manage tumor‐related symptoms or to prevent treatment‐related toxicity, available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC. Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone, the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens.     

NVP-BEZ235在肺癌中的研究及应用进展

NVP-BEZ235是一种新型磷脂酰肌醇3-激酶(PI3K)和哺乳动物雷帕霉素靶蛋白(mTOR)双重抑制剂,已有的研究结果证实NVP-BEZ235在肺癌治疗中联合其他药物有着较为理想的效果.对于EGFR突变肺癌亚型、KRAS突变肺癌亚型,NVP-BEZ235的治疗可能有潜在应用价值.     

Response to Subsequent Docetaxel in a Patient Cohort With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Acetate Treatment

Introduction/BackgroundDocetaxel or AA are therapeutic options for mCRPC. We retrospectively analyzed clinical outcomes with subsequent docetaxel in patients with mCRPC after disease progression (DP) with AA to evaluate cross resistance between these therapies.Patients and MethodsPatients with chemotherapy-naive mCRPC who were treated with AA in previously reported phase I to III trials, who had DP, and were subsequently treated (not on study) with docetaxel, were included. Acquired AA resistance was defined as: PSA decline > 50% from baseline or radiographically stable disease for ≥ 8 months, with subsequent DP. All other patients were defined as having primary AA resistance. Efficacy outcomes after docetaxel therapy were analyzed.ResultsWe identified 23 patients who were treated with docetaxel after DP with AA, including 14 (61%) with acquired and 9 (39%) with primary AA resistance. Median duration between discontinuation of AA and docetaxel initiation was 2.7 months (range, 0.2-14.7 months). Subsequent docetaxel therapy led to ≥ 30% PSA decline in 15 patients (65%) and ≥ 50% PSA decline in 11 patients (48%). Median OS from date of first docetaxel dose was 12.4 months (95% confidence interval, 8.2-19.6). Patients with previous primary versus acquired AA resistance had similar outcomes with subsequent docetaxel therapy.ConclusionIn this retrospective analysis, the type of AA resistance did not appear to affect outcomes with subsequent docetaxel. The PSA response rates observed suggest a lack of cross-resistance between docetaxel and AA, but prospective studies are needed to evaluate for potential cross-resistance and optimize sequences of therapy in patients with mCRPC.     

eRADicAte: A Prospective Evaluation Combining Radium-223 Dichloride and Abiraterone Acetate Plus Prednisone in Patients With Castration-Resistant Prostate Cancer

Background

Multiple castration-resistant prostate cancer (CRPC) therapies are approved by the United States Food and Drug Administration. Radium-223 dichloride (Ra-223) with abiraterone acetate plus prednisone have different mechanisms of action and distinct off-target side-effect profiles. We prospectively investigated their combined safety, tolerability, and patient-reported outcome measures.

Evaluation of Response to Enzalutamide Consecutively After Abiraterone Acetate/Prednisone Failure in Patients With Metastatic Castration-resistant Prostate Cancer

Introduction

Treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly during the past decade, and the preferred combination and/or sequence of these treatments remains controversial. In this retrospective study, we explored clinical and pathologic factors that could predict response to consecutive treatment with enzalutamide (ENZA) after disease progression (PD) on abiraterone acetate and prednisone (AA/P).

The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer

Introduction

The cardiovascular toxicity related to abiraterone and enzalutamide has been previously studied by our group. In this analysis, we aim to update our previous findings related to abiraterone and enzalutamide, including the new available evidence, both in castration-resistant and hormone-sensitive prostate cancer.

Metastatic Castration-Resistant Prostate Cancer: Two Case Reports of Dramatic Response with Abiraterone Acetate in Patients Heavily Pretreated with Chemotherapy

Metastatic castration-resistant prostate cancer (mCRPC) with visceral involvement requires new, effective and safe treatments after chemotherapy failure. The CYP17A1 inhibitor abiraterone acetate has been approved as a treatment for mCRPC, both after docetaxel chemotherapy and more recently for patients who are not responding to chemotherapy. In published studies, most patients previously treated with docetaxel had received a limited number of lines of chemotherapy and a small proportion of these patients presented with visceral metastases. We report two mCRPC patients with extensive visceral disease, who were heavily pretreated with chemotherapy. They experienced major responses to treatment with abiraterone acetate. For both patients, responses to abiraterone were noticeable within 1 month, encompassing a marked regression of visceral metastases and a decrease in prostate-specific antigen. The clinical benefit of abiraterone was maintained for at least 6 months and the treatment was well tolerated.Key words: Abiraterone acetate, Metastatic castration-resistant prostate cancerCytochrome P450 c17, Prostate-specific antigen, Chemotherapy     

Very Fast Recovery of Acute Disseminated Intravascular Coagulation with Abiraterone Acetate in a Patient with Bone Metastases from Castrate-Resistant Prostate Cancer

Disseminated intravascular coagulation (DIC) is a rare, potentially life-threatening complication of advanced prostate carcinoma. We report the successful treatment with abiraterone acetate of acute DIC related to a progressive bone metastatic disease in a chemotherapy-naïve patient with castrate-resistant prostate cancer.Key Words: Abiraterone acetate, Bone metastases, Castrate-resistant prostate cancer, Disseminated intravascular coagulation     

PUMA mediates the combinational therapy of 5-FU and NVP-BEZ235 in colon cancer

Colon cancer is the third most common cancer in humans which has a high mortality rate, and 5-Fluorouracil (5-FU) is one of the most widely used drugs in colon cancer therapy. However, acquired chemoresistance is becoming the major challenges for patients, and the molecular mechanism underlying the development of 5-FU resistance is still poorly understood. In this study, a newly designed therapy in combination with 5-FU and NVP-BEZ235 in colon cancer cells (HCT-116 and RKO) was established, to investigate the mechanism of 5-FU resistance and optimize drug therapy to improve outcome for patients. Our results show 5-FU induced cell apoptosis through p53/PUMA pathway, with aberrant Akt activation, which may well explain the mechanism of 5-FU resistance. NVP-BEZ235 effectively up-regulated PUMA expression, mainly through inactivation of PI3K/Akt and activation of FOXO3a, leading to cell apoptosis even in the p53^−/− HCT-116 cells. Combination treatment of 5-FU and NVP-BEZ235 further increased cell apoptosis in a PUMA/Bax dependent manner. Moreover, significantly enhanced anti-tumor effects were observed in combination treatment in vivo. Together, these results demonstrated that the combination treatment of 5-FU and NVP-BEZ235 caused PUMA-dependent tumor suppression both in vitro and in vivo, which may promise a more effective strategy for colon cancer therapy.     

The Effect of LMWH (Nadroparin) on Tumor Progression

Recent clinical studies on patients with malignancies, who were treated with UHF and LMWHs raised the possibility, that these agents may possess an inhibitory effect on tumor progression. Further studies supported that this effect is independent from the anticoagulant and antithrombotic action. In this retrospective study oncological patients with an increased risk for thromboembolism were choosen, who received prophylactic treatment with an LMWH (nadroparin) at least for 6 months. Comparing with the control group, in some subgroups (T3 and T4, as well as M1) the LMWH-treated patients showed a significantly increased survival.     

Cardiovascular and Metabolic Toxicity of Abiraterone in Castration-resistant Prostate Cancer: Post-marketing Experience

IntroductionAbiraterone improves survival in metastatic castration-resistant prostate cancer (mCRPC) but may result in the development or worsening of comorbid conditions. We assessed the course of these conditions in patients receiving abiraterone in clinical practice and compared outcomes with those in clinical trials.Materials and MethodsMedical records of patients with mCRPC who started abiraterone at an academic institution between 2012 and 2015 were reviewed for emergency department (ED) visits, hospitalizations, and the development and/or worsening of key comorbid conditions while on abiraterone. Patient characteristics and adverse events were compared with those from clinical trials.ResultsIn a cohort of 174 patients, 28% experienced either the development or worsening of a comorbid disease; 8% required an ED visit or hospitalization owing to known adverse effects of abiraterone. Increasing age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17), higher prostate-specific antigen at initiation of treatment (OR, 1.68; 95% CI, 1.18-2.47), preexisting uncontrolled hypertension (OR, 7.61; 95% CI, 1.22-38.70), congestive heart failure (OR, 7.61; 95% CI, 1.22-38.70), and cardiac arrhythmias (OR, 4.73; 95% CI, 1.39-15.12) were associated with increased odds of an ED visit or hospitalization owing to known adverse effects of abiraterone. The rate of discontinuation (6%) was similar to 1 phase III trial that demonstrated the drug’s efficacy in chemotherapy-naive patients.ConclusionFew patients discontinued abiraterone owing to toxicity; however, the fact that over one-quarter of patients experienced the development or worsening of cardiovascular and metabolic diseases warrants development of team-based approaches to the management of these comorbid conditions.     

Molecular Mechanisms of Tumor Angiogenesis and Tumor Progression

The formation of new blood vessels (angiogenesis) is crucial for the growth and persistence of primary solid tumors and their metastases. Furthermore, angiogenesis is also required for metastatic dissemination, since an increase in vascular density will allow easier access of tumor cells to the circulation. Induction of angiogenesis precedes the formation of malignant tumors, and increased vascularization seems to correlate with the invasive properties of tumors and thus with the malignant tumor phenotype. In the last few years, the discovery and characterization of tumor-derived angiogenesis modulators greatly contributed to our understanding of how tumors regulate angiogenesis. However, although angiogenesis appears to be a rate-limiting event in tumor growth and metastatic dissemination, a direct connection between the induction of angiogenesis and the progression to tumor malignancy is less well understood. In this review, we discuss the most recent observations concerning the modulation of angiogenesis and their implications in tumor progression, as well as their potential impact on cancer therapy.