Tankyrase regulates epithelial lumen formation via suppression of Rab11 GEFs

Rab11 GTPase proteins are required for cytokinesis, ciliogenesis, and lumenogenesis. Rab11a is critical for apical delivery of podocalyxin (PODXL) during lumen formation in epithelial cells. SH3BP5 and SH3BP5L are guanine nucleotide exchange factors (GEFs) for Rab11. We show that SH3BP5 and SH3BP5L are required for activation of Rab11a and cyst lumen formation. Using proximity-dependent biotin identification (BioID) interaction proteomics, we have identified SH3BP5 and its paralogue SH3BP5L as new substrates of the poly-ADP-ribose polymerase Tankyrase and the E3 ligase RNF146. We provide data demonstrating that epithelial polarity via cyst lumen formation is governed by Tankyrase, which inhibits Rab11a activation through the suppression of SH3BP5 and SH3BP5L. RNF146 reduces Tankyrase protein abundance and restores Rab11a activation and lumen formation. Thus, Rab11a activation is controlled by a signaling pathway composed of the sequential inhibition of SH3BP5 paralogues by Tankyrase, which is itself suppressed by RNF146.

Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics

IDH wild-type glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. Tackling this, we investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. Surprisingly, high anti-apoptotic BCL-xL and MCL-1expression correlated with heightened susceptibility of GBM to BCL-2 family protein-targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3-mimetics.

Sorafenib as a second-line treatment in metastatic renal cell carcinoma in Mexico: a prospective cohort study

Background Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). Methods A prospective observational cohort in Mexico (2012–2019). We included 132 subjects with metastatic RCC and who had progression despite treatment with sunitinib. The primary end-point was time to disease progression as evaluated every 12–16 weeks. Results The mean age of the cohort was 59 years (interquartile range [IQR] 50–72), 96 (73%) were men, and 48 (36%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.6 months (95% confidence interval [CI]: 6.7–10.5) and 40 months (95% CI: 34.5–45.4) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 58.2–83.8). On multivariable analyses, age > 65 years was associated with a longer PFS (HR 0.51; 95% CI: 0.31–0.86; p = 0.018). The median PFS in subjects aged > 65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2–18.8] vs. 7.2 months [95% CI: 5.3–9.1]; p = 0.012). Adverse events grade ≥ 3 associated with sorafenib occurred in 38 (29%) patients. Conclusion Sequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 years old.

Sorafenib as a Second-Line Treatment in Metastatic Renal Cell Carcinoma in Mexico: A Prospective Cohort Study

Background: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI).Methods: A prospective observational cohort in Mexico (2012–2019). We included 132 subjects with metastatic RCC and who had progression despite treatment with sunitinib. The primary end-point was time to disease progression as evaluated every 12–16 weeks.Results: The mean age of the cohort was 59 years (interquartile range [IQR] 50-72), 96 (73%) were men, and 48 (36%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.6 months (95% confidence interval [CI]: 6.7–10.5) and 40 months (95% CI: 34.5–45.4) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 58.2–83.8). On multivariable analyses, age >65 years was associated with a longer PFS (HR 0.51; 95% CI: 0.31-0.86; p = 0.018). The median PFS in subjects aged >65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2–18.8] vs. 7.2 months [95% CI: 5.3–9.1]; p = 0.012). Adverse events grade ≥3 associated with sorafenib occurred in 38 (29%) patients.Conclusion: Sequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects >65 years old.

Sorafenib as a Second-Line Treatment in Metastatic Renal Cell Carcinoma in Mexico: A Prospective Cohort Study

Background: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). Methods: A prospective observational cohort in Mexico (2012–2019). We included 132 subjects with metastatic RCC and who had progression despite treatment with sunitinib. The primary end-point was time to disease progression as evaluated every 12–16 weeks. Results: The mean age of the cohort was 59 years (interquartile range [IQR] 50-72), 96 (73%) were men, and 48 (36%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.6 months (95% confidence interval [CI]: 6.7–10.5) and 40 months (95% CI: 34.5–45.4) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 58.2–83.8). On multivariable analyses, age >65 years was associated with a longer PFS (HR 0.51; 95% CI: 0.31-0.86; p = 0.018). The median PFS in subjects aged >65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2–18.8] vs . 7.2 months [95% CI: 5.3–9.1]; p = 0.012). Adverse events grade ≥3 associated with sorafenib occurred in 38 (29%) patients. Conclusion: Sequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects >65 years old.

Sorafenib as a Second-Line Treatment in Metastatic Renal Cell Carcinoma in Mexico: A Prospective Cohort Study

Background: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI).Methods: A prospective observational cohort in Mexico (2012–2019). We included 148 subjects with metastatic RCC and who had progression despite treatment with sunitinib (n = 144) or pazopanib (n = 4). The primary end-point was time to disease progression as evaluated every 12–16 weeks.Results: The mean age of the cohort was 58 years (interquartile range [IQR] 48-68), 104 (70%) were men, and 51 (35%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.5 months (95% confidence interval [CI]: 6.8–10.2) and 40.1 months (95% CI: 35.2–45.0) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 63.9–79.4). On multivariate analyses, age >65 years was associated with a longer PFS (HR 0.57; 95% CI: 0.35-0.93; p = 0.025). The median PFS in subjects aged >65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2–17.9] vs. 7.2 months [95% CI: 5.5–8.9]; p = 0.018). Adverse events grade ≥3 associated with sorafenib occurred in 42 (28%) patients.Conclusion: Sequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects >65 years old.

Sorafenib as second-line treatment in metastatic renal cell carcinoma: A prospective cohort.

e17077 Background: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with advanced or metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a 2nd-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). Methods: Prospective observational cohort in Mexico City (July 2012 to July 2019). We included 148 subjects with metastatic RCC, treated by nephrectomy and who had RCC progression despite treatment with sunitinib (n = 144) or pazopanib (n = 4). All patients received sorafenib 400 mg orally twice a day on a continuous dosing schedule until disease progression or intolerable toxicity. The primary endpoint was time to progression evaluated every 12-16 weeks. Risk factors were classified according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC-RF) prognostic model. Results: Mean age of cohort was 58±10 years, 104 (70%) were male, 51 (35%) had none of IMDC-risk factors, and the most common sites of metastasis before sorafenib treatment were lung (n = 79, 53%) and bone (n = 30, 20%). The median progression-free survival and survival after the introduction of sorafenib treatment was 8.5 months (95% IC 6.8-10.2) and 40.1 months (95% IC 35.2-45.0) respectively. Median overall survival from RCC diagnosis to death was 71 months (95% CI 63.9-79.4). Median progression-free survival was longer in advanced RCC with none IMDC-RF compared with subjects with ≥2 IMDC-RF (10.3 [95%CI 6.1-14.6] vs 7.9 [95%CI 5.8-9.9] mo. respectively, p = 0.035). Age > 65 decreased risk of progression after sorafenib therapy (OR 0.33, 95% CI 0.14-0.77, p = 0.010). Median progression-free survival in subjects > 65 yrs old was longer (14 months, 95% CI 9.2-17.9) compared to subjects ≤65 yrs (7.2 months, 95% CI 5.5-8.9, p = 0.018). Adverse events associated to sorafenib occurred in 118 (80%) subjects: hand-foot syndrome (n = 118, 80%), diarrhea (n = 113, 76%), hypothyroidism (41, 28%), and mucositis (84, 57%). Any adverse events corresponding to a grade > 2 occurred in 48 (32%) patients. Conclusions: Sequential inhibition of VEGF with sorafenib as a 2nd-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 yrs old. Further clinical trials are needed.