Mechanism-Driven and Clinically Focused Development of Botanical Foods as Multitarget Anticancer Medicine: Collective Perspectives and Insights from Preclinical Studies, IND Applications and Early-Phase Clinical Trials

Cancer progression and mortality remain challenging because of current obstacles and limitations in cancer treatment. Continuous efforts are being made to explore complementary and alternative approaches to alleviate the suffering of cancer patients. Epidemiological and nutritional studies have indicated that consuming botanical foods is linked to a lower risk of cancer incidence and/or improved cancer prognosis after diagnosis. From these observations, a variety of preclinical and clinical studies have been carried out to evaluate the potential of botanical food products as anticancer medicines. Unfortunately, many investigations have been poorly designed, and encouraging preclinical results have not been translated into clinical success. Botanical products contain a wide variety of chemicals, making them more difficult to study than traditional drugs. In this review, with the consideration of the regulatory framework of the USFDA, we share our collective experiences and lessons learned from 20 years of defining anticancer foods, focusing on the critical aspects of preclinical studies that are required for an IND application, as well as the checkpoints needed for early-phase clinical trials. We recommend a developmental pipeline that is based on mechanisms and clinical considerations

Mechanism-Driven and Clinically Focused Development of Botanical Foods as Multitarget Anticancer Medicine: Collective Perspectives and Insights from Preclinical Studies, IND Applications and Early-Phase Clinical Trials

Cancer progression and mortality remain challenging because of current obstacles and limitations in cancer treatment. Continuous efforts are being made to explore complementary and alternative approaches to alleviate the suffering of cancer patients. Epidemiological and nutritional studies have indicated that consuming botanical foods is linked to a lower risk of cancer incidence and/or improved cancer prognosis after diagnosis. From these observations, a variety of preclinical and clinical studies have been carried out to evaluate the potential of botanical food products as anticancer medicines. Unfortunately, many investigations have been poorly designed, and encouraging preclinical results have not been translated into clinical success. Botanical products contain a wide variety of chemicals, making them more difficult to study than traditional drugs. In this review, with the consideration of the regulatory framework of the USFDA, we share our collective experiences and lessons learned from 20 years of defining anticancer foods, focusing on the critical aspects of preclinical studies that are required for an IND application, as well as the checkpoints needed for early-phase clinical trials. We recommend a developmental pipeline that is based on mechanisms and clinical considerations

Time from definitive therapy to onset of metastatic disease predicts outcomes in men with metastatic hormone sensitive prostate cancer.

PURPOSE: Contemporary treatment for metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) plus abiraterone or docetaxel. While these intensified regimens have improved efficacy, they are also associated with increased cost and toxicities. Not all men with mHSPC may be candidates for these intensified regimens, yet there are no clinical models or biomarkers used to optimize treatment selection. Herein, we hypothesized that longer time from prior definitive therapy (DT), either radical prostatectomy, definitive radiotherapy, or both, to onset of metastatic disease is associated with improved survival outcomes in men with newly diagnosed mHSPC. METHODS: This multicenter retrospective study included men initiating systemic therapy with ADT for new mHSPC. Kaplan-Meier and COX proportional hazard models assessed time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) by receipt of prior DT. RESULTS: Of the 253 men with new mHSPC, 115 (45%) had received prior DT. In a multivariate analysis, increasing years from DT to the start of ADT was an independent predictor of time to mCRPC (per year: hazard ratio 0.91 95% confidence interval 0.84-0.99, P = 0.020) and improved OS (per year: hazard ratio 0.87, 95% confidence interval 0.74-0.99, P = 0.0025) in patients with new mHSPC, and may assist with risk stratification in these patients at time of mHSPC. CONCLUSION: Time from DT to start of ADT is an independent predictor of time to mCRPC and OS in men with new mHSPC, and may assist with risk stratification of these patients for systemic therapy selection

Diagnostic Performance and Safety of 18F-rhPSMA-7.3 Positron Emission Tomography in Men With Suspected Prostate Cancer Recurrence: Results From a Phase 3, Prospective, Multicenter Study (SPOTLIGHT)

PURPOSE: SPOTLIGHT (NCT04186845) evaluated diagnostic performance and safety of radiohybrid MATERIALS AND METHODS: Men with prostate cancer recurrence underwent positron emission tomography/CT 50-70 minutes after intravenous administration of 296%±20% MBq RESULTS: The overall CONCLUSIONS

Serum Biomarkers of Bone Metabolism in Castration-Resistant Prostate Cancer Patients With Skeletal Metastases: Results From SWOG 0421

BackgroundPrior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421).MethodsMarkers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test.ResultsSera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005).ConclusionsSerum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy

The Impact of Late LHRH Agonist Dosing on Testosterone Suppression in Prostate Cancer Patients: An Analysis of US Clinical Data.

PURPOSE: Evaluate timeliness of androgen deprivation therapy dosing, impact of dosing non-adherence on testosterone (T) and frequency of T/prostate-specific antigen (PSA) testing in prostate cancer (PCa) patients. MATERIALS AND METHODS: Retrospective analyses of 22,860 PCa patients treated with luteinizing hormone-releasing hormone (LHRH) agonists. Analyses used two definitions of \u27Month\u27: \u2728 Day Month\u27 (\u27Late\u27: dosing after day 28, 84, 112, or 168) and \u27Extended Month\u27 (\u27Late\u27 after day 32, 97, 128, or 194) for 1-, 3-, 4-, and 6-month formulations, respectively. Prevalence of \u27Late\u27 dosing, associated T values and frequency of T/PSA testing were assessed. Statistical significance was tested using unpaired t-test. RESULTS: 84% of injections were \u27Late\u27 for \u2728 Day Month\u27 and 27% for \u27Extended Month\u27. For \u2728 Day Month\u27, 60% and 29% of injections were \u27Late\u27 by \u3e1 and \u3e2 weeks. 4% of T were \u3e50ng/dL for \u27Early/On-Time\u27 injections using both definitions. 15% and 27% of T were \u3e50ng/dL when \u27Late\u27, for \u2728 Day Month\u27 and \u27Extended Month\u27, respectively. For \u27Early/On-Time\u27 vs. \u27Late\u27, 22% vs. 31% of T were \u3e20ng/dL for \u2728 Day Month\u27 and 21% vs. 43% for \u27Extended Month\u27. Mean T were higher when \u27Late\u27 (49ng/dL for \u2728 Day Month\u27, 79ng/dL for \u27Extended Month\u27) vs. \u27Early/On-Time\u27 (21ng/dL for both). 83% of injections had PSA measurements, only 13% a T assessment. CONCLUSIONS: LHRH agonists were frequently (84%) administered later than schedules used in pivotal trials. Nearly half of \u27Late\u27 T (\u27Extended Month\u27) were \u3e20ng/dL; mean T almost doubled castration level. Elevated T levels remain unidentified with infrequent testing

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing