Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naïve, Metastatic, Castration-Resistant Prostate Cancer

Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor-targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes

Using circulating tumor cells to advance precision medicine in prostate cancer

The field of circulating tumor cell (CTC) enrichment has seen many emerging technologies in recent years, which have resulted in the identification and monitoring of clinically relevant, CTC-based biomarkers that can be analyzed routinely without invasive procedures. Several molecular platforms have been used to investigate the molecular profile of the disease, from high throughput gene expression analyses down to single cell biological dissection. The established presence of CTC heterogeneity nevertheless constitutes a challenge for cell isolation as the several subpopulations can potentially display different molecular characteristics; in this scenario, careful consideration must be given to the isolation approach, whereas methods that discriminate against certain subpopulations may result in the exclusion of CTCs that carry biological relevance. In the context of prostate cancer, CTC molecular interrogation can enable longitudinal monitoring of key biological features during treatment with substantial clinical impact, as several biomarkers could predict tumor response to AR signaling inhibitors (abiraterone, enzalutamide) or standard chemotherapy (taxanes). Thus, CTCs represent a valuable opportunity to personalize medicine in current clinical practice

Substrate mediated interaction between pairs of keratocytes: Multipole traction force models describe their migratory behavior.

A series of traction force microscopy experiments involving pairs of keratocytes migrating on compliant substrates were analyzed. We observed several instances where keratocytes that are about to collide turn before they touch. We term this phenomenon collision avoidance behavior and we propose that the turning is caused by the substrate mediated elastic interactions between the cells. A multipole analysis of the cell traction reveals that the left-right symmetry of the keratocyte traction pattern is broken during collision avoidance events. The analysis further shows that the cell migration direction reorients before the principal traction dipoles as the cells turn. Linear elasticity theory is used to derive the cell-cell interaction energy between pairs of keratocytes. The traction force applied by each cell is modeled as a two points (dipole) or three points (tripod) force model. We show that both models predict that cells that are about to collide in a head-on manner will turn before touching. The tripod model is further able to account for the quadrupole components of the traction force profile that we observed experimentally. Also, the tripod model proposes a mechanism that may explain why cells tend to scatter with a finite angle after a collision avoidance event. A relationship between the scattering angle and the traction force quadrupole moment is also established. Dynamical simulations of migrating model cells are further used to explain the emergence of other cell pair trajectories that we observed experimentally

Quantitative analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRXL301, a nanoparticle of docetaxel

Aim: We reviewed the radiographic response of three patients with metastatic castration-resistant prostate cancer treated with CRXL301, a docetaxel nanoparticle. For these three patients, we isolated and analyzed circulating tumor cells (CTCs) to explore microtubule (MT) drug-target engagement (MT-DTE) as a biomarker of response to treatment. MT-DTE was based on a quantitative assessment of the MT cytoskeleton in CTCs from pre- and post-treatment patient samples as a potential read-out of CRXL301 activity.Methods: We isolated CTCs using negative CD45+ depletion and subjected them to multiplex confocal microscopy using our established protocol. CTCs were identified as CD45-/CK+/DAPI+ cells and MT-DTE was determined using our developed imaging algorithm. We quantified MT bundling in CTCs across multiple time points, from baseline to on-treatment to disease progression. Here, we describe the longitudinal analysis of MT-DTE in CTCs from patients treated with CRXL301 and its correlation with response to treatment.Results: We collected CTCs at seven time points from three metastatic castration-resistant prostate cancer patients. Clinical response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria in those patients with measurable disease. Of the three patients enrolled, one experienced partial response (-50%) to CRXL301 and two patients were unevaluable given bone only disease. Notably, however, these two patients showed stable disease clinically based on bone scans. MT-DTE across all time points revealed that, early time points within four and 24 h of drug administration exhibited the highest levels of drug engagement (MT-DTE) as compared to baseline. However, these early time points did not correlate with clinical response. We observed that the CTCs collected one week after the first or second dose of CRXL301 treatment in the responding patient had numerically higher levels of MT-DTE as compared to the other two patients.Conclusion: Taxane on-target activity can be detected and analyzed quantitatively in CTCs by tubulin immunofluorescence. Early time points, within 24 h of drug administration, showed high levels of DTE but did not correlate with clinical response. MT-DTE in CTCs collected after one week on treatment correlated best with treatment response. The clinical utility of the 1-week CTC DTE should be tested and validated in future clinical trials involving taxanes