Kelli Bullard Dunn

Postoperative Adjuvant Chemotherapy Use in Patients With Stage II/III Rectal Cancer Treated With Neoadjuvant Therapy: A National Comprehensive Cancer Network Analysis

PURPOSEnPractice guidelines recommend that patients who receive neoadjuvant chemotherapy and radiation for locally advanced rectal cancer complete postoperative adjuvant systemic chemotherapy, irrespective of tumor downstaging.nnnPATIENTS AND METHODSnThe National Comprehensive Cancer Network (NCCN) Colorectal Cancer Database tracks longitudinal care for patients treated at eight specialty cancer centers across the United States and was used to evaluate how frequently patients with rectal cancer who were treated with neoadjuvant chemotherapy also received postoperative systemic chemotherapy. Patient and tumor characteristics were examined in a multivariable logistic regression model.nnnRESULTSnBetween September 2005 and December 2010, 2,073 patients with stage II/III rectal cancer were enrolled in the database. Of these, 1,193 patients receiving neoadjuvant chemoradiotherapy were in the analysis, including 203 patients not receiving any adjuvant chemotherapy. For those seen by a medical oncologist, the most frequent reason chemotherapy was not recommended was comorbid illness (25 of 50, 50%); the most frequent reason chemotherapy was not received even though it was recommended or discussed was patient refusal (54 of 74, 73%). After controlling for NCCN Cancer Center and clinical TNM stage in a multivariable logistic model, factors significantly associated with not receiving adjuvant chemotherapy were age, Eastern Cooperative Oncology Group performance status ≥ 1, on Medicaid or indigent compared with private insurance, complete pathologic response, presence of re-operation/wound infection, and no closure of ileostomy/colostomy.nnnCONCLUSIONnEven at specialty cancer centers, a sizeable minority of patients with rectal cancer treated with curative-intent neoadjuvant chemoradiotherapy do not complete postoperative chemotherapy. Strategies to facilitate the ability to complete this third and final component of curative intent treatment are necessary.

Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is often dose limiting. In addition, the effects of chemotherapy are nonspecific, targeting both malignant and normal tissues. As a result, recent efforts increasingly have focused on developing agents that target specific molecules in tumor cells in order to both improve efficacy and limit toxicity. This review summarizes the history and current use of targeted molecular therapy for cancer, with a special emphasis on recently developed inhibitors of Focal Adhesion Kinase (FAK).

Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy

Focal adhesion kinase (FAK) increasingly has been implicated in cancer growth and progression. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that blocks the Y397 autophosphorylation site. FAK inhibitor, Y15 decreased Y397 FAK in different colon cancer cells lines in a dose-dependent manner. In addition, Y15 decreased phosphorylated Src in SW480 and SW620 cells. Y15 decreased cell viability, increased detachment, and increased apoptosis in SW480 and SW620 cells in vitro. Combination of FAK inhibitor Y15 and Src inhibitor PP2 decreased colon cancer cell viability more effectively than each agent alone. In addition, when combined with 5-FU, oxaliplatin or 5-FU and oxaliplatin, colon cancer viability was decreased further, demonstrating that dual and triple therapy synergistically inhibits cell viability. In vivo, Y15 decreased subcutaneous SW620 tumor growth by 28%. Combination of oral Y15 with 5-FU/or oxaliplatin decreased tumor growth by 48% more effectively than each inhibitor alone. Finally, tumors treated with Y15 expressed less Y397 phosphorylation, Src phosphorylation and had greater apoptosis than controls. Thus, the small molecule FAK inhibitor, Y15, inhibits cell growth in vitro and in vivo and enhances the efficacy of chemotherapy, demonstrating that it can be an effective therapeutic inhibitor for treating colon cancer.

FAK and HAS Inhibition Synergistically Decrease Colon Cancer Cell Viability and Affect Expression of Critical Genes

Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3 inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation. We sought to determine the genes affected by HAS and FAK inhibition and hypothesized that dual inhibition would synergistically inhibit viability. Y15 (FAK inhibitor) and the HAS inhibitor 4-methylumbelliferone (4-MU) decreased viability in a dose dependent manner; viability was further inhibited by treatment with Y15 and 4-MU in colon cancer cells. HAS inhibited cells treated with 2 μM of Y15 showed significantly decreased viability compared to HAS scrambled cells treated with the same dose (p < 0.05) demonstrating synergistic inhibition of viability with dual FAK/HAS inhibition. Microarray analysis showed more than 2-fold up- or down-regulation of 121 genes by HAS inhibition, and 696 genes by FAK inhibition (p < 0.05) and revealed 29 common genes affected by both signaling. Among the genes affected by FAK or HAS3 inhibition were genes, playing role in apoptosis, cell cycle regulation, adhesion, transcription, heatshock and WNT pathways. Thus, FAK or HAS inhibition decreases SW620 viability and affects several similar genes, which are involved in the regulation of tumor survival. Dual inhibition of FAK and HAS3 decreases viability to a greater degree than with either agent alone, and suggests that synergistic inhibition of colon cancer cell growth can result from affecting similar genetic pathways.

Management of Bowel Obstruction in Patients with Stage IV Cancer: Predictors of Outcome After Surgery

BackgroundPatients with stage IV cancer and bowel obstruction (BO) present a complicated management problem. We sought to determine if specific parameters could predict outcome after surgery.MethodsRecords of patients with stage IV cancer and BO treated from 1991 to 2008 were reviewed. For surgical patients, 30-day morbidity and 90-day mortality were assessed using exact multivariable logistic regression methods.ResultsOf 198 patients, 132 (66.7 %) underwent surgery, 66 medical treatment alone, and demographics were similar. A total of 41 patients (20.7 %) were diagnosed with stage IV cancer and BO synchronously, all treated surgically; the remaining presented metachronously. Medically managed patients were more likely to have received chemotherapy in the 30xa0days prior to BO (45 of 66 [68.2 %] vs 40 of 132 [30.3 %], pxa0<xa0.01). In the surgical group, 30-day morbidity was 35.6 %, while 90-day mortality was 42.3 %. Median overall survival for synchronous patients was 14.1xa0months (95 % confidence interval [95 % CI] 7.6–23.2), and 3.7xa0months (95 % CI 2.5–5.2) and 3.6xa0months (95 % CI 1.5–5.2) for metachronous patients treated surgically and medically, respectively. A multivariate model for 90-day surgical mortality identified low serum albumin, metachronous presentation, and ECOGxa0>xa01 as predictors of death (pxa0<xa0.05). A model for 30-day surgical morbidity yielded low hematocrit as a predictive factor (pxa0<xa0.05).ConclusionsThis cohort identifies characteristics indicative of morbidity and mortality in stage IV cancer and BO. Low serum albumin, ECOGxa0>xa01, and metachronous presentation predicted for 90-day surgical mortality. These data suggest factors that can be used to frame treatment discussion plans with patients.

Biomarkers and targeted therapeutics in colorectal cancer.

The development of colorectal cancer is characterized by a multitude of molecular events that can occur through the pathways of loss of heterozygosity, microsatellite instability, and CpG-island methylation. The accumulation of these molecular events ultimately results in polyps formed from previously normal mucosa to develop the fundamental characteristics of cancerization: uncontrolled proliferation, growth, and invasion. Advances in the understanding of molecular events leading to colorectal cancer have led to the development of biomarkers, patient-specific and tumor-specific molecular signatures that have potential as tools for accurate risk assessment, personalized treatment planning, development of targeted agents, and evaluation of treatment response.

Colorectal Cancer: Adjuvant Therapy

The stage of disease at presentation is the most important predictor of outcome for colon cancer patients. Stage I (T1-2N0M0) disease carries an excellent prognosis of up to 95% 5-year survival rate after resection, and surgical treatment alone is considered sufficient; adjuvant treatment is not indicated.1 Patients with stage II disease (T3-4N0M0) also have excellent 5-year survival, averaging 70–80%, but a subset of high-risk patients have poorer prognosis.1 As such, it has been suggested that some stage II patients may benefit from adjuvant therapy, but the role of treatment in this patient population remains controversial. In contrast, adjuvant treatment repeatedly has been shown to improve survival for stage III (TanyN1-2M0) disease.

Abstract C184: A small molecule FAK inhibitor increases the cytotoxicity of 5-fluorouracil.

Introduction: Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that has been implicated in colon cancer progression. We have shown that SW620 colon cancer cells express both FAK and activated (phosphorylated) Y397 FAK. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that decreases cell viability and tumor growth in vivo. Because chemotherapy for colon cancer is based upon regimens containing 5-fluorouracil (5-FU), we hypothesized that combining Y15 with 5-FU would synergistically inhibit colon cancer cell viability and growth in vitro and in vivo. Methods: SW620, SW480 and HCT116 colon cancer cells grown in culture were treated with Y15 and 5-FU alone and in combination. In vitro viability was assessed with an MTT assay. To test the in vivo affects of these agents, SW620 cells were injected into the flank of female nude mice. The mice were then treated with either Y15 (100mg/kg oral gavage), 5-FU (30mg/kg intraperitoneal injection), combination Y15+5-FU, or PBS control (30mg/kg intraperitoneal injection). Tumors were measured with calipers every 3 days and tumor volumes calculated. Results: MTT assays demonstrated synergistic inhibition of cell viability with combination Y15+5-FU treatment. The viability of SW620 cells treated with 2microM of Y15 and 50microM of 5-FU was significantly less than that of cells treated with either agent alone (p Conclusions: The small molecule FAK inhibitor, Y15, increases the cytotoxic activity of 5-FU against colon cancer cells in vitro. In vivo, at a dose where neither agent decreases tumor growth, the combination of Y15 and 5-FU significantly inhibits tumor growth. These data suggest that Y15 augments the effect of 5-FU and suggests that the addition of this small molecule FAK inhibitor may be a good therapeutic adjunct for treating colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C184.