Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.

Repeatability and Reproducibility Assessment of the Apparent Diffusion Coefficient in the Prostate: A Trial of the ECOG-ACRIN Research Group (ACRIN 6701).

BACKGROUND: Uncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion-weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within-subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation. PURPOSE: Evaluation of the repeatability (same-day) and reproducibility (multi-day) of whole-prostate and focal-lesion ADC assessment in a multi-site setting. STUDY TYPE: Prospective multi-institutional. SUBJECTS: Twenty-nine males, ages 53 to 80 (median 63) years, following diagnosis of prostate cancer, 10 with focal lesions. FIELD STRENGTH/SEQUENCE: 3T, single-shot spin-echo diffusion-weighted echo-planar sequence with four b-values. ASSESSMENT: Sites qualified for the study using an ice-water phantom with known ADC. Readers performed DWI analyses at visit 1 ("V1") and visit 2 ("V2," 2-14 days after V1), where V2 comprised scans before ("V2pre") and after ("V2post") a "coffee-break" interval with subject removal and repositioning. A single reader segmented the whole prostate. Two readers separately placed region-of-interests for focal lesions. STATISTICAL TESTS: Reproducibility and repeatability coefficients for whole prostate and focal lesions derived from median pixel ADC. We estimated the wCV and 95% confidence interval using a variance stabilizing transformation and assessed interreader reliability of focal lesion ADC using the intraclass correlation coefficient (ICC). RESULTS: The ADC biases from b0 -b600 and b0 -b800 phantom scans averaged 1.32% and 1.44%, respectively; mean b-value dependence was 0.188%. Repeatability and reproducibility of whole prostate median pixel ADC both yielded wCVs of 0.033 (N = 29). In 10 subjects with an evaluable focal lesion, the individual reader wCVs were 0.148 and 0.074 (repeatability) and 0.137 and 0.078 (reproducibility). All time points demonstrated good to excellent interreader reliability for focal lesion ADC (ICCV1  = 0.89; ICCV2pre  = 0.76; ICCV2post  = 0.94). DATA CONCLUSION: This study met the QIBA claim for prostate ADC. Test-retest repeatability and multi-day reproducibility were largely equivalent. Interreader reliability for focal lesion ADC was high across time points. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2 TOC CATEGORY: Pelvis.

A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers.

PURPOSE: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. PATIENTS AND METHODS: Sixty men were treated with alisertib 50 mg twice daily for 7 days every 21 days. Eligibility included metastatic prostate cancer and at least one: small-cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; or elevated serum neuroendocrine markers. The primary endpoint was 6-month radiographic progression-free survival (rPFS). Pretreatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed. RESULTS: Median PSA was 1.13 ng/mL (0.01-514.2), number of prior therapies was 3, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%), and AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3-13). Exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora-N-myc complex disruption. CONCLUSIONS: Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.

Functional outcomes following robotic prostatectomy using athermal, traction free risk-stratified grades of nerve sparing.

OBJECTIVE: To report our unique approach for individualizing robotic prostate cancer surgery by risk stratification and sub classification of the periprostatic space into 4 distinct compartments, and thus performing 4 precise different grades of nerve sparing based on neurosurgical principles and to present updated potency and continence outcomes data of patients undergoing robotic-assisted laparoscopic prostatectomy (RALP) using our risk-stratified approach based on layers of periprostatic fascial dissection. PATIENTS AND METHODS: (1) Between January 2005 and December 2010, 2,536 men underwent RALP by a single surgeon at our institution. (2) Included patients were those with ≥ 1-year follow-up and were preoperatively continent and potent, defined as having a SHIM questionnaire score of >21; thus, the final number of patient in the study cohort was 1,335. (3) Postoperative potency was defined as the ability to have successful intercourse (score of ≥ 4 on question 2 of the SHIM); continence was defined as the use of no pads per 24 h. RESULTS: (1) The potency and continence for NS grades 1, 2, 3, and 4 were found to be 90.6, 76.2, 60.5, and 57.1 % (P < 0.001) and 98, 93.2, 90.1, and 88.9 % (P < 0.001), respectively. (2) The overall PSM rates for patients with NS grades 1, 2, 3, and 4 were 10.5, 7, 5.8, and 4.8 %, respectively (P = 0.064). CONCLUSIONS: The study found a correlation between risk-stratified grades of NS technique and continence and potency. Patients with lesser grades of NS had higher rates of potency and continence.

Role of magnetic resonance imaging in bladder cancer: current status and emerging techniques.

OBJECTIVES: To evaluate the current status of magnetic resonance imaging (MR) as a staging tool for bladder cancer. To investigate the role of MR in assessing chemotherapeutic response in bladder cancer patients. PATIENTS AND METHODS: A Pubmed/MEDLINE search was conducted to identify original articles, review articles, and editorials regarding the use of MR in bladder cancer. RESULTS: Contrast-enhanced MR and diffusion weighted MR (DW-MRI) can likely distinguish between non-muscle invasive bladder cancer and muscle invasive cancer with >80% accuracy. Some advantages of DW-MRI are the differentiation of benign versus malignant tissue involvement without the need for intravenous contrast, and the possibility of obtaining information on histologic grade and T stage. Traditional MR sequence have low sensitivity for identifying small lymph node metastases but MR lymphography (MRL) using ultra-small paramagnetic iron oxide (USPIO) may enhance their detectin. There may be a role for DW-MRI in the evaluation of chemotherapeutic response in bladder cancer patients. CONCLUSION: To date, sample sizes and study designs are insufficient to clearly establish the role of MR in bladder cancer management, and to this end, well designed prospective trials are needed.