FDA-approved enzalutamide is commonly prescribed to reduce the growth of advanced prostate cancer by blocking androgen receptor function. However, enzalutamide-resistant prostate cancer (ERPC) ...invariably develops and progresses to metastatic, lethal disease. Management of ERPC poses a special problem not only because available therapeutic regimens cannot effectively kill ERPC cells but also due to their propensity to invade large bones. Moreover, molecular mechanism(s) behind enzalutamide resistance is not properly understood, which is delaying development of newer agents. We found that the pseudokinase, Tribbles 2 (TRIB2), is overexpressed in ERPC cells and plays a critical role in their survival. Forced overexpression of TRIB2 enhances prostate cancer cell growth and confers resistance to physiologic doses of enzalutamide, suggesting that TRIB2 plays an important role in the development and progression of ERPC. Though TRIB2 has emerged as an excellent molecular target for ERPC, suitable inhibitors are not commercially available for effective targeting. By designing a luciferase-tagged TRIB2 fusion protein-based assay system, we screened a library of about 1,600 compounds and found that daclatasvir (DCV), an antiviral drug, effectively inhibits TRIB2-luciferase. We also found that DCV degrades TRIB2 proteins by direct binding and resensitizes ERPC cells to enzalutamide treatment. Moreover, DCV at lower, sublethal doses synergizes with enzalutamide to decrease the viability and induce apoptosis in prostate cancer cells. Because DCV is already approved by the FDA and well tolerated in humans, based on our findings, it appears that DCV is a promising new agent for development of an effective therapy for advanced, enzalutamide-resistant, lethal prostate cancer.
E-Cigarette Use Among Adolescents Hwang, Clara; O'Neil, Jean
Journal for nurse practitioners,
June 2020, 2020-06-00, 20200601, Letnik:
16, Številka:
6
Journal Article
Recenzirano
The rapid increase of battery-operated electronic cigarettes (also known as e-cigarettes) among the adolescent population has become an epidemic and a leading public health concern. Inhalation of the ...aerosol produced by e-cigarettes, also known as vaping, exposes users to a variety of additives that include nicotine, tetrahydrocannabinol, cannabinoid, and other chemicals. Adolescents are especially vulnerable to the harmful effects of nicotine. In addition to promoting nicotine dependence, e-cigarette use has been linked to e-cigarette, or vaping, product use-associated lung injury. Screening for e-cigarette use should be done at each adolescent visit to ensure appropriate resources and education are provided.
•E-cigarette use can cause fatal respiratory problems.•Nicotine is present in vaping devices.•There is increased use of e-cigarettes in adolescents.•Nicotine can have negative effects on the adolescent brain.
5049 Background: Disease progression following novel hormonal therapy in CRPC remains bone-dominant and D-responsive. D + Ra223 would be a logical combination but myelosuppression is dose-limiting. ...Prior combinations have required a reduction in dose intensity (DI) in both agents. Fractionated schedules of D Q2weekly (DQ2) have comparable activity to D 75mg/m 2 Q3weekly with mitigated myelosuppression. We hypothesized that a fractionated schedule of DQ2 with standard Ra223 dosing would be feasible while preserving DI. Methods: Subjects had progressive bone-metastatic CRPC, ECOG PS 0-2, and no bulky visceral disease. Design was phase I, 6+6, dose escalation plus expansion with 28-day cycles. DQ2 was given in a 4-week lead-in, then with Ra223 every 4 weeks. Dose-level (DL) 1: D 40mg/m 2 ; if neutropenia, then 1a: D 40mg/m 2 with G-CSF on Day 16, 2a: D 50mg/m 2 with G-CSF on Day 16. Up to 6 cycles of the combination were given. Primary objective was the feasibility and maximum tolerated DL explored (MTD). Secondary objectives included PSA response, ORR, PFS, OS, and quality of life. Results: 43 patients (pts) enrolled including 34.9% non-white pts and 76.7% with ≥ 4 bony mets. 8 dropped out during the D lead in (1 each neutropenia, stroke, failure to thrive, anorexia/fatigue, thrombocytopenia, infusion reaction and 2 hospitalized for other reasons). At DL1, 2 of 3 had DLT (both neutropenia). No DLT occurred at DL1a (n=5) or DL2a (n=5). MTD was DL2a. 22 subjects enrolled to expansion cohort at DL2a. Of the 35 pts treated with D + Ra223, adverse events of interest listed in the table. No febrile neutropenia, fractures, or G5 toxicity were seen. 19/35 completed all 6 cycles of combination therapy. PSA50 response was seen in 18 (51.4%) and PSA90 in 9 (25.7%) pts. Of 31 pts with evaluable data, best response (RECIST 1.1) was 1 CR, 5 PR, 23 SD, 2 PD. Median PFS was 50.0 weeks (95% CI: 37.3-86.1) and OS was 86.1 weeks (95% CI: 60.0-130.9). 10 pts progressed exclusively in nodal/visceral metastases compared to 6 in bone only. Quality of life measures remained stable on study. Conclusions: Utilizing a D lead-in strategy, combination DQ2 and Ra223 was feasible and well tolerated, with a favorable PFS and evidence of preferential control of osseous metastases. Dose-intensity for both docetaxel and Ra223 was preserved and comparable to the FDA-approved dose-schedules for each of the single agents. The lead-in design and use of G-CSF contributes significantly to the feasibility. Clinical trial information: NCT03737370 . Table: see text
5062 Background: Guideline recommended genetic testing in advanced prostate cancer (PC) is underutilized and not always accepted by patients (pts). We assessed attitudes and decisional conflict (DC) ...surrounding genetic testing associated with subsequent test completion, and differences between white and nonwhite pts. Methods: Eligibility for this prospective single institution study included pts with N1 or M1 PC who had not yet completed genetic testing. Upon informed consent, pts were given a 24-question survey using a Likert scale of 0 (strongly agree) to 4 (strongly disagree) to assess attitudes toward genetic testing including a validated assessment of DC. DC and DC subscores (range 0-100, with 100 being highest DC) were calculated from subsets of survey responses. Self-identified race was obtained from the EMR. Two-group comparisons between white and nonwhite pts, and between those who completed genetic testing and who did not, were conducted with SAS v9.4 software using Fisher’s exact test for categorical variables and Wilcoxon rank sum test for Likert scale survey questions and DC score variables. Results: Of 42 enrolled pts (21 white, 17 black, 1 Asian, 3 declined), 22 (52.4%) completed genetic testing. Compared to white pts, nonwhite pts expressed more concern about test result privacy (mean = 1.72 v 2.95, p = 0.002), test results being used for non-healthcare purposes (1.78 v 3.00, p = 0.003), and trying unproven treatments (1.72 v 2.67, p = 0.01). Nonwhite pts felt more external pressure in decision-making compared to white pts (0.67 v 0.29, p = 0.04). No significant differences were appreciated in completion of testing, DC, or any subscore between racial groups. Compared to pts who did not complete testing, those who completed testing were more likely to report they knew which options were available (0.73. v 1.25, p = 0.05), knew the benefits of each option (0.77 v 1.30, p = 0.04), knew the risk and side effects of each option (0.95 v 1.50, p = 0.05), were clear about which benefits matter most to themselves (0.73 v 1.37, p = 0.02), and were clear about the best choice for themselves (0.73 v 1.35, p = 0.02). DC (28.59 v 18.11, p = 0.03) was higher in pts who did not complete testing, along with uncertainty (31.25 v 19.32, p = 0.02) and informed (31.25 v 20.45, p = 0.03) subscores. No differences were seen in values clarity, support, or effective decision subscores. Conclusions: In our study, nonwhite pts expressed greater concern about privacy, data misuse, and trying unproven treatments. Those who did not complete testing had more DC with greater uncertainty about knowledge and decision making. These findings will help direct targeted interventions to increase knowledge, trust, and decisional certainty about genetic testing in pts with advanced PC. Ongoing studies will assess the impact of these interventions on rates of testing completion at our institution.
Abstract
Prostate cancer is the most common malignancy and the 2nd leading cause of cancer death in men worldwide. First-line treatment includes androgen deprivation therapy in addition to androgen ...receptor (AR) antagonists that work to block androgen signaling. Although most patients respond initially to hormone deprivation therapy, responses are not durable and the disease progresses to a lethal stage, termed castrate resistant prostate cancer (CRPC). Interestingly, most CRPCs are still dependent on AR signaling for growth and survival, therefore more potent AR-antagonists such as enzalutamide have recently been FDA approved for treatment of CRPC. However, response rates to enzalutamide can be limited by emergence of acquired resistance or intrinsic resistance. A universal mechanism of resistance to cytotoxic therapies is upregulation of anti-apoptotic programs that function to override death signals and permit survival of the tumor cell. In prostate cancer, overexpression of the Inhibitor of Apoptosis (IAP) proteins cIAP1, cIAP2, and XIAP has been demonstrated in progression to CRPC. Additionally, aberrant expression of these proteins is reported to contribute to anti-androgen resistance. Therefore, to achieve more robust responses to AR inhibition with enzalutamide, we targeted IAP proteins in order to amplify the apoptotic signal and increase cell death in prostate cancer cells. Using a small-molecule IAP inhibitor, we evaluated response to enzalutamide upon IAP inhibition in prostate cancer cell lines LNCAP and C4-2. Here we demonstrate greater proliferation inhibition, reduced cell survival and synergistic induction of apoptosis signaling in response to combined AR antagonism and IAP inhibition. Furthermore, we demonstrate depletion of cIAP1 protein expression upon enzalutamide treatment indicating a possible role for AR in regulating anti-apoptotic pathways. Taken together these results demonstrate that IAP proteins may be a critical survival pathway in CRPC and antagonism of these proteins through small-molecule inhibition can amplify apoptosis and increase cell death in response to enzalutamide. Targeting a critical survival pathway can lower the apoptotic threshold providing a possible therapeutic opportunity to treat and prevent resistance to enzalutamide and increase benefit to patients with this lethal form of prostate cancer.
Citation Format: Amanda Pilling, Ok Hwang, Clara Hwang. Targeted suppression of inhibitor of apoptosis proteins amplifies apoptosis and improves response to enzalutamide in prostate cancer. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3571.
Background
Inactivating alterations in SPOP frequently occur in prostate cancer and promote increased dependency on androgen receptor (AR)‐mediated oncogenic signaling. The presence of SPOP mutation ...(SPOP‐mutant SPOP‐mut) may therefore impact therapeutic outcomes with AR‐directed therapies and docetaxel in metastatic castration‐resistant (mCRPC).
Methods
This was a retrospective study of mCRPC patients treated at an urban academic hospital (n = 103). Patients underwent tumor DNA sequencing to determine SPOP mutational status (SPOP‐mut). Outcomes measured were overall survival (OS) from diagnosis and treatment with second‐generation AR signaling inhibitor (ARSI) or docetaxel and time to PSA progression (prostate‐specific antigen‐progression‐free survival PSA‐PFS) compared by SPOP status using Kaplan–Meier curves and log‐rank test. The univariable and multivariable Cox proportional hazard model evaluated the association of SPOP mutation and outcomes adjusted for clinicopathologic features.
Results
SPOP‐mut was associated with longer PSA‐PFS in mCRPC (median 1.79 vs. 0.84 years; p = 0.06) and multivariate analysis (hazard ratio HR = 0.37; 95% confidence interval CI: 0.17–0.84; p = 0.02). SPOP‐mut demonstrated a higher median PSA decline compared to SPOP wild‐type (median decline 100% vs. 92%, p = 0.02). SPOP‐mut was not associated with OS from the start of ARSI or docetaxel (median OS not reached vs. 2.0 years) or PSA‐PFS on docetaxel (median PSA‐PFS 0.4 vs. 0.5 years) in mCRPC. The majority of SPOP mutations were identified in African American (AA) patients (69.2%) compared to Caucasian patients (30.8%). Race‐associated multivariate analysis revealed no significant differences in OS from the start of ARSI or the start of docetaxel and no differences in ARSI or docetaxel PSA‐PFS between AA and Caucasian patients. Molecular profiling demonstrated that AA patients had a higher frequency of SPOP mutations and greater heterogeneity of SPOP variants within the coding sequence. Analysis of concurrent genomic alterations revealed that SPOP mutations co‐occur with APC mutations (p = 0.001) and alterations in the Wnt pathway (p = 0.017).
Conclusions
Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race‐associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker‐directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients.
Objectives. Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment ...options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo.
Methods. A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction.
Results. Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline.
Conclusions. Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.
Background
Despite multiple treatment advances for castration‐resistant prostate cancer (CRPC), there are currently no curative therapies and patients ultimately to succumb to the disease. Docetaxel ...(DTX) is the standard first‐line chemotherapy for patients with metastatic CRPC; however, drug resistance is inevitable and often develops rapidly, leading to disease progression in nearly all patients. In contrast, when DTX is deployed with androgen deprivation therapy in castration‐sensitive disease, more durable responses and improved outcomes are observed, suggesting that aberrant androgen receptor (AR) signaling accelerates DTX resistance in CRPC. In this study, we demonstrate that AR dysregulates the mitotic checkpoint, a critical pathway involved in the anticancer action of DTX.
Methods
Androgen‐dependent and independent cell lines were used to evaluate the role of AR in DTX resistance. Impact of drug treatment on cell viability, survival, and cell‐cycle distribution were determined by plate‐based viability assay, clonogenic assay, and cell‐cycle analysis by flow cytometry, respectively. Mitotic checkpoint kinase signal transduction and apoptosis activation was evaluated by Western blotting. Pathway gene expression analysis was evaluated by RT‐PCR. A Bliss independence model was used to calculate synergy scores for drug combination studies.
Results
Activation of AR in hormone‐sensitive cells induces a rescue phenotype by increasing cell viability and survival and attenuating G2/M arrest in response to DTX. Analysis of mitotic checkpoint signaling shows that AR negatively regulates spindle checkpoint signaling, resulting in premature mitotic progression and evasion of apoptosis. This phenotype is characteristic of mitotic slippage and is also observed in CRPC cell lines where we demonstrate involvement of AR splice variant AR‐v7 in dysregulation of checkpoint signaling. Our findings suggest that DTX resistance is mediated through mechanisms that drive premature mitotic exit. Using pharmacologic inhibitors of anaphase‐promoting complex/cyclosome and polo‐like kinase 1, we show that blocking mitotic exit induces mitotic arrest, apoptosis, and synergistically inhibits cell survival in combination with DTX.
Conclusion
Our results suggest that targeting the mechanisms of dysregulated mitotic checkpoint signaling in AR‐reactivated tumors has significant clinical potential to extend treatment benefit with DTX and improve outcomes in patients with lethal prostate cancer.
Abstract only
TPS175
Background: Disease progression following highly-active androgen-axis therapy (HAAT) in CRPC remains bone-dominant and docetaxel-responsive. Combination bone-homing Ra223 isotope ...therapy with docetaxel would be a logical combination therapy to follow but myelosuppression is dose-limiting. With 3-weekly bolus schedules of docetaxel (D), dose-reduction to 60mg/m2 Q3wkly and Ra223 to every 6 weeks has been required representing a reduction in the dose-intensity of both agents. Fractionated schedules of docetaxel Q2wkly (DQ2) have comparable activity to D 75mg/m2 Q3wkly (DQ3) with mitigated myelosuppression. We hypothesize that a fractionated dose-schedule of DQ2 in combination with standard Ra223 dosing will be feasible without reduction in dose-intensity of Ra-223 or D. Methods: Outcomes: The primary objective is to determine the feasibility and maximal tolerated dose (MTD) of the combination. Secondary objectives include PSA kinetics, objective response, bone marker outcomes, progression free and overall survival, and description of toxicity and quality of life. Eligibility: Progressive bone-metastatic CRPC, ECOG PS 0-2 with no prior Ra223, no prior docetaxel for CRPC, and no bulky visceral disease. Design: Phase I (6+6) design; 4 week lead-in with DQ2. Dose-level 1a: 40mg/m2; 2a: 50mg/m2, both with PEGylated G-CSF on Day 16. If tolerated (≤ Grade 2 toxicity, ANC ≥ 1500, Platelets ≥ 100,000), lead-in is followed by C1D1 of DQ2 plus Ra223 Q4wkly x 6 doses. Dose level 1a has accrued 6 subjects without DLT. Enrollment to Dose Level 2a began in August, 2020. An expansion cohort of 25 subjects is planned after the MTD is determined. Clinical trial information: NCT03737370.
Abstract only
160
Background: Predictive markers linking molecular background to treatment response and clinical outcomes are currently lacking in prostate cancer. Missense mutations in SPOP ...(speckle-type POZ protein) define a distinct molecular subtype, occurring in about 12% of both clinically localized and metastatic disease. SPOP mutations occur early in prostate tumorigenesis and facilitate dysregulation of the androgen-receptor (AR) signaling network, suggesting mutant SPOP can impact response to AR-directed therapies. We hypothesized that SPOP mutation will be associated with superior response to next-generation AR inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Methods: This is a retrospective study to evaluate patients who progressed to mCRPC and were treated with AR-targeted therapy (i.e. enzalutamide, abiraterone acetate). Eligibility criteria inlcuded androgen deprivation therapy, metastatic disease documented by bone lesion or soft tissue identified on imaging, castrate testosterone level ( < 50g/dL), and evaluable tissue for DNA analysis. SPOP status was determined by next-generation sequencing. Time to PSA progression (PSA TTP) was defined per PCWG2 as PSA increase of 25% from nadir and a minimum of 2 ng/ml calculated from date of primary treatment initiation to the date of PSA progression. Overall survival (OS) was calculated from start of treatment to date of death. Statisitcal comparision of the SPOP mutant or wild-type was determined using Kaplan-Meier and independent t-test analysis. Results: The analysis included 69 men with mCRPC with previous or ongoing ADT and receipt of AR-directed therapy (aberaterone acetate, enzalutamide). SPOP status was determined for all patients: 7 patients SPOP mutant, 62 patients SPOP wild-type. Mutant SPOP was associated with significantly longer PSA TTP (22.5 vs. 9.7 months, p = 0.031) and improved OS (21 vs. 29 months, p = 0.12) with enzalutamide or abiraterone as compared to SPOP wild-type patients. Conclusions: Our data demonstrate that SPOP mutations predict for better outcomes with next-generation AR inhibitors in men with mCRPC. SPOP mutations are a prominent molecular sub-type with potential to impact clinical management in men with metastatic, therapy resistant prostate cancer.
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