Active surveillance of metastatic renal cell carcinoma: Results from a prospective observational study (MaRCC).

BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination.

BACKGROUND: New therapies are being explored as therapeutic options for men with biochemically recurrent prostate cancer (BRPC) who wish to defer androgen deprivation therapy. MPX is pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. METHODS: In the phase I portion of this phase I/II study, non-metastatic BRPC patients were assigned to increasing doses of MPX (Muscadine Naturals. Inc., Clemmons, NC) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Initial dose selection was based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. The primary endpoint was the recommended phase II dosing regimen. RESULTS: The cohort (n = 14, 71% Caucasian, 29% black) had a median follow-up of 19.2 (6.2-29.7) months, median age of 61 years, and median Gleason score of 7. Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 eructation. No other related adverse events were reported and one patient reported improvement of chronic constipation. Six of 14 patients came off study for disease progression (five metastatic, one rising PSA) after exposure for a median of 15 months. One patient came off for myasthenia gravis that was unrelated to treatment. Seven patients remain on study. The lack of dose-limiting toxicities led to the selection of 4,000 mg/d as the highest dose for further study. Median within-patient PSADT increased by 5.3 months (non-significant, P = 0.17). No patients experienced a maintained decline in serum PSA from baseline. CONCLUSION: These data suggest that 4,000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low-dose (500 mg) and high-dose (4,000 mg) MPX are being further investigated in a randomized, multicenter, placebo-controlled, dose-evaluating phase II trial.

Screening assay for blood vessel maturation inhibitors.

In cancer patients, the development of resistance to anti-angiogenic agents targeting the VEGF pathway is common. Increased pericyte coverage of the tumor vasculature undergoing VEGF targeted therapy has been suggested to play an important role in resistance. Therefore, reducing the pericytes coverage of the tumor vasculature has been suggested to be a therapeutic approach in breaking the resistance to and increasing the efficacy of anti-angiogenic therapies. To screen compound libraries, a simple in vitro assay of blood vessel maturation demonstrating endothelial cells and pericytes association while forming lumenized vascular structures is needed. Unfortunately, previously described 3-dimensional, matrix based assays are laborious and challenging from an image and data acquisition perspective. For these reasons they generally lack the scalability needed to perform in a high-throughput environment. With this work, we have developed a novel in vitro blood vessel maturation assay, in which lumenized, vascular structures form in one optical plane and mesenchymal progenitor cells (10T1/2) differentiate into pericyte-like cells, which associate with the endothelial vessels (HUVECs). The differentiation of the 10T1/2 cells into pericyte-like cells is visualized using a GFP reporter controlled by the alpha smooth muscle actin promoter (SMP-8). The organization of these vascular structures and their recruited mural cells in one optical plane allows for automated data capture and subsequent image analysis. The ability of this assay to screen for inhibitors of pericytes recruitment was validated. In summary, this novel assay of in vitro blood vessel maturation provides a valuable tool to screen for new agents with therapeutic potential.

Withaferin A is a potent inhibitor of angiogenesis.

The medicinal plant Withania somnifera is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In Ayurveda , the major Traditional Indian medicine system, extracts from W. somnifera are distinctively employed for the treatment of arthritis and menstrual disorders. Because these conditions involve angiogenic processes we hypothesized that the W. somnifera extracts might contain angiogenesis inhibitors. We employed an endothelial cell-sprouting assay to monitor the purification of substances from W. somnifera root extracts and isolated as the active principle the previously known natural product withaferin A. We show that withaferin A inhibits human umbilical vein endothelial cell (HUVEC) sprouting in three-dimensional collagen-I matrix at doses which are relevant to NF-kappa B-inhibitory activity. Withaferin A inhibits cell proliferation in HUVECs (IC50 =12 nM) at doses that are significantly lower than those required for tumor cell lines through a process associated with inhibition of cyclin D1 expression. We propose that the inhibition of NF-kappa B by withaferin A in HUVECs occurs by interference with the ubiquitin-mediated proteasome pathway as suggested by the increased levels of poly-ubiquitinated proteins. Finally, withaferin A is shown to exert potent anti-angiogenic activity in vivo at doses that are 500-fold lower than those previously reported to exert anti-tumor activity in vivo. In conclusion, our findings identify a novel mode of action of withaferin A, which highlights the potential use of this natural product for cancer treatment or prevention.