Gerald A. Gantt

Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A

Chemotherapy stimulates cancer-associated fibroblasts to secrete interleukin-17A to provide maintenance cues to support the growth of colorectal cancer-initiating cells.

Statin therapy is associated with improved pathologic response to neoadjuvant chemoradiation in rectal cancer.

BACKGROUND: Achieving a pathologic complete response to neoadjuvant chemoradiation improves prognosis in rectal cancer. Statin therapy has been shown to enhance the impact of treatment in several malignancies, but little is known regarding the impact on rectal cancer response to neoadjuvant chemoradiation. OBJECTIVE: The purpose of this study was to determine whether statin use during neoadjuvant chemoradiation improves pathologic response in rectal cancer. DESIGN: This was a retrospective cohort study based on data from a prospectively maintained colorectal cancer database. The 2 cohorts were defined by statin use during neoadjuvant chemoradiation. SETTING: This study was performed at a single tertiary referral center. PATIENTS: Four hundred seven patients with primary rectal adenocarcinoma who underwent neoadjuvant therapy then proctectomy between 2000 and 2012 were included. Ninety-nine patients (24.3%) took a statin throughout the entire course of neoadjuvant therapy. MAIN OUTCOME MEASURES: The primary outcome measure was pathologic response to neoadjuvant chemoradiotherapy as defined by the American Joint Committee on Cancer tumor regression grading system, grades 0 to 3. RESULTS: Patients in the statin cohort had a lower median regression grade (1 vs 2, p = 0.01) and were more likely to have a better response (grades 0–1 vs 2–3) than those not taking a statin (65.7% vs 48.7%, p = 0.004). Statin use remained a significant predictor of an American Joint Committee on Cancer grade 0 to 1 (OR, 2.25; 95% CI, 1.33–3.82) in multivariate analyses. Although statin use itself did not significantly improve oncologic outcomes, an American Joint Committee on Cancer grade 0 to 1 response was associated with statistically significant improvements in overall survival, disease-free survival, cancer-specific mortality, and local recurrence. LIMITATIONS: This was a retrospective study and subject to nonrandomization of patients and incorporated patients on variable statin agents and doses. CONCLUSIONS: Statin therapy is associated with an improved response of rectal cancer to neoadjuvant chemoradiation. These data provide the foundation for a prospective clinical trial.

Gene expression profile is associated with chemoradiation resistance in rectal cancer

Patients with rectal cancer who achieve a complete pathological response after preoperative chemoradiation (CRT) have an improved oncological outcome. Identifying factors associated with a lack of response could help our understanding of the underlying biology of treatment resistance. This study aimed to develop a gene expression signature for CRT‐resistant rectal cancer using high‐throughput nucleotide microarrays.

NPTX2 is associated with neoadjuvant therapy response in rectal cancer

BACKGROUND Neoadjuvant chemoradiation (CRT) is recommended for locally advanced rectal cancer. Tumor response varies from pathologic complete response (pCR) to no tumor regression. The mechanisms behind CRT resistance remain undefined. In our previously generated complementary DNA microarrays of pretreatment biopsies from rectal cancer patients, neuronal pentraxin 2 (NPTX2) expression discriminated patients with pCR from those with residual tumor. As tumor response is prognostic for survival, we sought to evaluate the clinical relevance of NPTX2 in rectal cancer. MATERIALS AND METHODS Real-time quantitative polymerase chain reaction was used to evaluate NPTX2 messenger RNA expression in individual rectal cancers before CRT. Tumors with NPTX2 expression <50% of normal rectum were defined as NPTX2-low and those with >50% were defined as NPTX2-high. NPTX2 levels were compared to response to therapy and oncologic outcomes using Mann-Whitney, Kruskal-Wallis, chi-square, and Mantel-Cox (log-rank) tests, as appropriate. RESULTS Rectal cancers from 40 patients were included. The mean patient age was 56.8 years, and 30% were female. pCR was achieved in eight of 40 patients (20%). In these patients, messenger RNA NPTX2 levels were significantly decreased compared to those with residual cancer (fold change 30.4, P = 0.017). Patients with NPTX2-low tumors (n = 13) achieved improved response to treatment (P = 0.012 versus NPXT2-high tumors), with 38.5% and 46.1% of patients achieving complete or moderate response, respectively. Of patients with NPTX2-high tumors (n = 27), 11.1% and 18.5% achieved complete or moderate response, respectively. No recurrence or death was recorded in patients with NPTX2-low tumors, reflecting more favorable disease-free survival (P = 0.045). CONCLUSIONS Decreased NPTX2 expression in rectal adenocarcinomas is associated with improved response to CRT and improved prognosis. Further studies to validate these results and elucidate the biological role of NPTX2 in rectal cancer are needed.

PARP inhibition sensitizes colorectal cancer-initiating cells to chemotherapy: PARP Inhibition and Chemosensitivity

Colorectal cancer (CRC) remains a leading killer in the U.S. with resistance to treatment as the largest hurdle to cure. Colorectal cancer‐initiating cells (CICs) are a self‐renewing tumor population that contribute to tumor relapse. Here, we report that patient‐derived CICs display relative chemoresistance compared with differentiated progeny. In contrast, conventional cell lines failed model therapeutic resistance. CICs preferentially repaired chemotherapy‐induced DNA breaks, prompting us to interrogate DNA damage pathways against which pharmacologic inhibitors have been developed. We found that CICs critically depended on the key single‐strand break repair mediator, poly(ADP‐ribose) polymerase (PARP), to survive treatment with standard‐of‐care chemotherapy. Small molecule PARP inhibitors (PARPi) sensitized CICs to chemotherapy and reduced chemotherapy‐treated CIC viability, self‐renewal, and DNA damage repair. Although PARPi monotherapy failed to kill CICs, combined PARPi therapy with chemotherapy attenuated tumor growth in vivo. Clinical significance of PARPi for CRC patients was supported by elevated PARP levels in colorectal tumors compared with normal colon, with further increases in metastases. Collectively, our results suggest that PARP inhibition serves as a point of fragility for CICs by augmenting therapeutic efficacy of chemotherapy. Stem Cells 2019;37:42–53