Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5061-5061 ◽  
Author(s):  
J. Araujo ◽  
A. J. Armstrong ◽  
E. L. Braud ◽  
E. Posadas ◽  
M. Lonberg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Interactions ◽  
Bone Alkaline Phosphatase ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Best Response ◽  
Bone Scans ◽  
And Migration

5061 Background: Dasatinib, a potent inhibitor of SRC family kinases, inhibits in vitro prostate cancer cell proliferation and migration. Consistent with those findings are the clinical observations that osteoclast activity and bone turnover are downregulated in patients treated with dasatinib. We report promising preliminary results of dasatinib in combination with docetaxel (D) for treatment of metastatic castration-resistant prostate cancer (CRPC). Methods: Male pts with progressive CRPC and castrate levels of testosterone (≤50 ng/dL) requiring chemotherapy were enrolled. Escalating doses of dasatinib (50–120 mg QD) and D (60–75 mg/m2 Q 21 days) were evaluated (n = 16) followed by enrollment of 30 pts at the phase 2-selected dose (100 mg dasatinib QD + D at 75 mg/m2 Q 21 days). Continuation of bisphosphonates was permitted; anti-androgens were discontinued. Primary endpoint (Ph. 2) was to determine drug-drug interactions. Secondary endpoints were: changes in PSA, bone scans and tumor size, bone metabolism [urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP)] and PK. Results: 46 pts were treated with 28 pts still on therapy. Median treatment duration (n = 18, pts off study) was 4.2 months (0.13–9.63). Preliminary analysis showed no interaction between dasatinib and D. PSA response was seen in 13/32 (41%) pts, clinical benefit (PR + SD) for RECIST-evaluable pts was 21/21, [7 PR, 5 uPR and 4 SD (at ≥21 wks) and 5 SD at ≥6 wk)]. Of 31 pts with bone scans, 30 patients had a best response of either improved (32%) or stable (65%) at ≥6 weeks. For pts with measurable bone markers levels, 12/26 (46%) had a ≥35% decrease in uNTX and 17/24 (71%) had a decrease in BAP from baseline. 6 of 42 pts experienced ≥ grade 3 adverse events (AEs), including fatigue, myelosuppression and pleural effusion (n = 1). Most common grade 1/2 AEs were fatigue, dysgeusia, GI, and skin disorders. Conclusions: Dasatinib and D at doses up to 120 mg QD and 75 mg/m2 are safe with manageable toxicities and no drug-drug interactions. These data confirm the antitumor and antiosteoclast activity of dasatinib in combination with D and serve as the basis for the ongoing phase III study of this combination. [Table: see text]

A phase II study of once-daily dasatinib for patients with castration-resistant prostate cancer (CRPC) (CA180085)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5147-5147 ◽  
Author(s):  
E. Yu ◽  
C. Massard ◽  
M. Gross ◽  
G. Wilding ◽  
E. Posadas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitor ◽  
Bone Alkaline Phosphatase ◽  
Bisphosphonate Therapy ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Once Daily ◽  
Psa Response ◽  
Bone Scans

5147 Background: Dasatinib is a potent oral SRC family kinase inhibitor that also inhibits c-KIT and PDGFR in vitro. The anti-proliferative/anti-metastatic activity as well as osteoclast inhibitory function of dasatinib in pre-clinical models supports its potential as a targeted therapy for prostate cancer. Previously we presented results on BID dosing of dasatinib in the treatment of CRPC (ASCO. 2008 Abstract 5156). A second group of patients (pts) was enrolled to investigate the activity, safety and bone effects of 100 mg once daily dosing. Methods: Male pts with progressive metastatic CRPC, rising PSA, castrate levels of testosterone (< 50 ng/dL) and no prior chemotherapy were enrolled. Dasatinib dose was 100 mg QD. Continuation of bisphosphonates was permitted. Primary endpoint was a composite of: PSA responses, bone scans and disease control by RECIST. Urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP) were determined Q 4-weeks as indicators of bone metabolism. Results: 47 pts were treated (median treatment duration was 2.3 months). 11 patients were evaluable by RECIST; of these 64% achieved SD. The composite response rate was (8/47) 17%. Of 22 pts with bone scans, 50% were stable at 12 weeks and 3/9 (33%) were stable at 24 weeks. A prolonged PSA doubling time was observed in 32 of 39 pts (82%), including one pt with a PSA response. Of the pts with evaluable bone markers, including those who continued on bisphosphonate therapy, 20/41 (49%) had a ≥ 35% decrease in uNTX and 21/42 (50%) had a decrease from baseline in BAP. Grade 3/4 adverse events (AEs) were experienced by 13% of pts (diarrhea, asthenia, and pleural effusion [n=1]). Grade 1/2 AEs (≥ 15% of pts) were diarrhea, nausea, headache, fatigue, asthenia, anorexia and dyspnea. Conclusions: Fewer and less severe AEs were observed in all categories for the QD dosing group compared to the previously reported BID dosing cohort. In addition, preliminary clinical activity (tumor and PSA response; decreasing bone turnover [uNTX, BAP]), is now confirmed to be similar in pts treated with 100mg QD and BID dosing. These data support the relevance of further studies of dasatinib in metastatic CRPC. [Table: see text]

Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone: A rationale for increasing drug exposure in castration-resistant prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4645-4645
Author(s):  
Nima Sharifi ◽  
Rui Li ◽  
Kristen Evaul ◽  
Kamalesh Sharma ◽  
Richard J Auchus
Keyword(s):  
Prostate Cancer ◽  
Drug Exposure ◽  
Nuclear Translocation ◽  
Hydroxysteroid Dehydrogenase ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Steroidogenic Enzymes ◽  
Xenograft Growth ◽  
Castration Resistant

4645 Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1,000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC50 of < 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.

Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone as a rationale for dose escalation in castration-resistant prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 209-209
Author(s):  
Nima Sharifi ◽  
Rui Li ◽  
Kristen Evaul ◽  
Kamalesh Sharma ◽  
Richard J Auchus
Keyword(s):  
Prostate Cancer ◽  
Dose Escalation ◽  
Nuclear Translocation ◽  
Hydroxysteroid Dehydrogenase ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Steroidogenic Enzymes ◽  
Xenograft Growth ◽  
Castration Resistant

209 Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC50 of < 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.

Bone metabolism biomarkers (BMB) and progression-free survival (PFS) in men with metastatic hormone-sensitive prostate cancer (HSPC): SWOG S1216, a phase III trial of androgen deprivation therapy (ADT) with or without orteronel.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5523-5523
Author(s):  
Primo Lara ◽  
Edward Mayerson ◽  
Erik Gertz ◽  
Catherine Tangen ◽  
Amir Goldkorn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Bone Alkaline Phosphatase ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Disease Extent ◽  
Phase Iii Trial ◽  
Correlative Analysis ◽  
Castration Resistant ◽  
Increased Risk

5523 Background: We previously reported that baseline BMB are independently prognostic for overall survival (OS) in men with castration resistant prostate cancer. We correlated BMB with outcomes in mHSPC as part of S1216, a phase III trial of ADT +/- the novel CYP17 inhibitor orteronel. Methods: Blood was obtained at study entry for bone resorption [C-telopeptide(CTx) & Pyridinoline(PYD)] & formation markers [C-terminal collagen propeptide(CICP) & bone alkaline phosphatase(BAP)]. With prior DSMC approval, patients were sampled to mask potential treatment effect. Logistic regression was used to assess if BMB elevation above median was prognostic for a PFS event w/in 2 years across pooled study treatment arms, adjusting for baseline variables (including disease extent, PSA, age, pre-randomization ADT, & presence of bone mets). An additional interaction term between BMB elevation & presence of bone mets was included; if significant, separate models were developed for men +/- bone mets. Results: Of 1,313 men, 656 were included in this analysis. All 4 BMB levels were higher in men with a PFS event w/in 2 years vs. those with no PFS event. The odds ratio (OR) for a PFS event was significantly higher in men w/ elevated baseline BMB (see table). For BAP, a significant interaction between marker elevation and bone mets was seen (p = 0.003); men w/ bone mets and BAP elevation had an OR of 1.83 for a PFS event in 2 years. Conclusions: In men with newly diagnosed HSPC, elevated baseline levels of BMB were significantly associated with PFS, with about a two-fold increased risk of a progression event w/in 2 years. For CICP, CTx, & PYD, this association was independent of the presence of bone metastases. Baseline BMB levels have strong prognostic value in the mHSPC context. Correlative analysis of BMB & OS is planned. Clinical trial information: NCT01809691 . [Table: see text]

scholarly journals SPP1 Promotes Enzalutamide Resistance and EMT Activation in CRPC Progression via PI3K/AKT and ERK1/2 Pathways

2021 ◽  
Author(s):  
Xiaocong Pang ◽  
Junling Zhang ◽  
Xu He ◽  
Yanlun Gu ◽  
Wei Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Strong Relationship ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
Castration Resistant ◽  
And Migration

Abstract The bottleneck arising from castration-resistant prostate cancer (CRPC) treatment is its high metastasis potential and anti-androgen drug resistance, which severely affects survival time of prostate cancer (PCa) patients. In our previous study, we firstly revealed SPP1 was a potential hub signature for predicting metastatic CRPC (mCRPC) development. Herein, we integrated multiple databases to explore the association of SPP1 expression with prognosis, survival, metastatic levels in CRPC progression, and also investigated SPP1 expression in PCa tissues and cell lines. Next, PCa cell lines with overexpression or depletion of SPP1 were established to study the effect of SPP1 on enzalutamide sensitivity, and adhesion and migration of prostate cancer cell lines and further explore the underlying regulatory mechanisms. Bioinformatics analysis, PCR, immunohistochemical staining and western blot results suggested SPP1 upregulation had strong relationship with the malignant progression of CRPC. SPP1 knockdown repressed enzalutamide sensitivity, invasion and migration of prostate cancer cells in vitro. Importantly, upregulating SPP1 promoted, while silencing SPP1 attenuated epithelial-mesenchymal-transition (EMT). Our results further demonstrate that SPP1 overexpression maintains the activation of PI3K/AKT signaling and ERK1/2 pathways. Overall, our findings unraveled the functional role and clinical significance of SPP1 in PCa progression, and help to discover new potential targets against mCRPC.

Discovering novel P38α inhibitors for the treatment of prostate cancer through virtual screening methods

2019 ◽  
Vol 11 (24) ◽  
pp. 3125-3137
Author(s):  
Kaiwen Li ◽  
Zean Li ◽  
Yiran Tao ◽  
Qiong Wang ◽  
Yiming Lai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Virtual Screening ◽  
Screening Methods ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Virtual Libraries ◽  
Mitogen Activated Protein ◽  
And Migration ◽  
New Anticancer Drugs

Aim: P38α plays a crucial role in the development of castration-resistant prostate cancer. Discovering novel inhibitors of P38α offers potential for the development of new anticancer drugs. Methods & results: Compounds from the Chemdiv and Enamine virtual libraries were filtered to construct the P38α inhibitor-like library. A total of 58 new P38α inhibitors were discovered via virtual screening; these included three compounds (compound 1, 5, 9) with kinase IC50 of below 10 μM. In vitro, these three compounds have the potential to suppress the viabilities of prostate cancer cell lines, however, only compound 9 can inhibit the proliferation and migration of prostate cancer cells. Conclusion: The potent compounds discovered in this study demonstrate anticancer functions by targeting the P38α mitogen-activated protein kinases signaling pathway and are worthy of further investigation.

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