BCL2L11 Induction Mediates Sensitivity to Src and MEK1/2 Inhibition in Thyroid Cancer.

Patients with advanced thyroid cancer, including advanced papillary thyroid cancer and anaplastic thyroid cancer (ATC), have low survival rates because of the lack of efficient therapies available that can combat their aggressiveness. A total of 90% of thyroid cancers have identifiable driver mutations, which often are components of the MAPK pathway, including BRAF, RAS, and RET-fusions. In addition, Src is a non-receptor tyrosine kinase that is overexpressed and activated in thyroid cancer, which we and others have shown is a clinically relevant target. We have previously demonstrated that combined inhibition of Src with dasatinib and the MAPK pathway with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells. Herein, we identified the pro-apoptotic protein BCL2L11 (BIM) as being a key mediator of sensitivity in response to combined dasatinib and trametinib treatment. Specifically, cells that are sensitive to combined dasatinib and trametinib treatment have inhibition of FAK/Src, MEK/ERK, and AKT, resulting in the dramatic upregulation of BIM, while cells that are resistant lack inhibition of AKT and have a dampened induction of BIM. Inhibition of AKT directly sensitizes resistant cells to combined dasatinib and trametinib but will not be clinically feasible. Importantly, targeting BCL-XL with the BH3-mimeitc ABT-263 is sufficient to overcome lack of BIM induction and sensitize resistant cells to combined dasatinib and trametinib treatment. This study provides evidence that combined Src and MEK1/2 inhibition is a promising therapeutic option for patients with advanced thyroid cancer and identifies BIM induction as a potential biomarker of response.

Targeting CDK4/6 Represents a Therapeutic Vulnerability in Acquired BRAF/MEK Inhibitor-Resistant Melanoma.

There is a clear need to identify targetable drivers of resistance and potential biomarkers for salvage therapy for patients with melanoma refractory to the combination of BRAF and MEK inhibition. In this study, we performed whole-exome sequencing on BRAF-V600E-mutant melanoma patient tumors refractory to the combination of BRAF/MEK inhibition and identified acquired oncogenic mutations in NRAS and loss of the tumor suppressor gene CDKN2A We hypothesized the acquired resistance mechanisms to BRAF/MEK inhibition were reactivation of the MAPK pathway and activation of the cell-cycle pathway, which can both be targeted pharmacologically with the combination of a MEK inhibitor (trametinib) and a CDK4/6 inhibitor (palbociclib). In vivo, we found that combination of CDK4/6 and MEK inhibition significantly decreased tumor growth in two BRAF/MEK inhibitor-resistant patient-derived xenograft models. In vitro, we observed that the combination of CDK4/6 and MEK inhibition resulted in synergy and significantly reduced cellular growth, promoted cell-cycle arrest, and effectively inhibited downstream signaling of MAPK and cell-cycle pathways in BRAF inhibitor-resistant cell lines. Knockdown of CDKN2A in BRAF inhibitor-resistant cells increased sensitivity to CDK4/6 inhibition alone and in combination with MEK inhibition. A key implication of our study is that the combination of CDK4/6 and MEK inhibitors overcomes acquired resistance to BRAF/MEK inhibitors, and loss of CDKN2A may represent a biomarker of response to the combination. Inhibition of the cell-cycle and MAPK pathway represents a promising strategy for patients with metastatic melanoma who are refractory to BRAF/MEK inhibitor therapy.

Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo.

Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF-directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single-agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF-mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients.

Acute renal failure due to phenazopyridine (Pyridium) overdose: case report and review of the literature.

Phenazopyridine (Pyridium) is a commonly used urinary tract analgesic. It has been associated with yellow skin discoloration, hemolytic anemia, methemoglobinemia, and acute renal failure, especially in patients with preexisting kidney disease. We report a 17-year-old female with vertically transmitted human immunodeficiency virus (HIV) infection, presenting with acute renal failure and methemoglobinemia following a suicidal attempt with a single 1,200 mg ingestion of Pyridium. She had no prior evidence of HIV nephropathy. The patient had a progressive nonoliguric renal failure on the 3rd day following the ingestion. She was treated with N-acetylcysteine, intravenous carnitine, and alkalinization of the urine. Her kidney biopsy revealed acute tubular necrosis with no glomerular changes. After 7 days of conservative management, she was discharged home with normal kidney function. To our knowledge, this is the second smallest amount of Pyridium overdose resulting in acute renal failure with no previous history of kidney disease.

El procedimiento de Ross para reemplazo valvular aórtico / The Ross procedure for aortic valve replacement

La valvulopatía Aórtica es común en la población y el substituto valvular óptimo no ha sido encontrado. Las válvulas mecánicas necesitan anticoagulación de por vida y las válvulas tisulares tienen limitada durabilidad. El reemplazo de la válvula aórtica por un autoinjerto pulmonar produce excelentes resultados en la mayoría de los pacientes. Se evaluó las condiciones postoperatorias tales como: mortalidad, complicaciones, estancia hospitalaria de los 32 pacientes operados por el procedimiento de Ross en el hospital Jackson Memorial y se comparó esos resultados con los de la literatura médica existente. El promedio de seguimiento fue de un año y 11 meses postcirugía. El 6.2 por ciento de los operados fallecieron. Las mayores complicaciones tempranas fueron síndrome postpericardiotomía, derrame pericárdico y atelectasias. El promedio de estancia hospitalaria fue de 10.8 días para los pacientes pediátricos y de 13.1 días para los adultos. Los seguimientos ecocardiográficos revelaron ausencia de gradientes significativos de presión a través del autoinjerto pulmonar. El autoinjerto pulmonar podría ser el mejor substituto disponible en niños y en todo paciente con valvulopatía aórtica y expectativa de vida mayor a 20 años.

Aortic valve disease is a common entity in the general population. The optimal substitute has not been found. Mechanical valves need life-long anticoagulation. Tissue valves have a limited durability. The replacement of the aortic valve by a pulmonary autograft produces excellent results in the majority of patients. The postoperatory conditions (Mortality, Complications, Hospital stay) of 32 patients who underwent the Ross procedure at Jackson Memorial Hospital were evaluated and the results compared to the ones existing in the medical literature. The average follow-up was one year and 11 months. Six percent of the patients died. The major complications were: post-pericardiotomy syndrome, pericardial effusion and atelectasis. The average pediatric and adult hospital stays were 10.8 and 13.1 days respectively. Echocardiography follow-ups showed absence of any significant pressure gradient through the pulmonary autograft. The pulmonary autograft might be the most suitable substitute available for children and for every patient with aortic valve disease and a life expectancy longer than 20 years.