Minsig Choi

Preclinical studies of apogossypolone, a novel pan inhibitor of Bcl-2 and Mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells

Objective: Overexpression of antiapoptotic Bcl-2 family proteins confers resistance to conventional therapy in pancreatic cancer patients. Apogossypolone (ApoG2) is an analogue of (−)−gossypol, exhibiting binding activity with Ki values of 35 nmol/L for Bcl-2 and 25 nmol/L for Mcl-1. The present study was designed to test our hypothesis whether inactivation of Bcl-2 family of proteins using ApoG2 could sensitize pancreatic cancer cells to the cytotoxic effect of gemcitabine. Methods: Two pancreatic cancer cell lines were treated with ApoG2, gemcitabine, and their combination; cytotoxicity and apoptosis was confirmed by MTT and histone/DNA enzyme-linked immunosorbent assay. Coimmunoprecipitation experiments were performed to elucidate the mechanism of action of ApoG2. In vivo efficacy of ApoG2 was evaluated in a xenograft model to confirm its therapeutic benefit with gemcitabine. Results: When ApoG2 was combined with gemcitabine, increased cytotoxicity and apoptosis was evident. Coimmunoprecipitation experiment revealed that ApoG2 blocks the heterodimerization of Mcl-1/Bax and Bcl-2/Bim in cells. Furthermore, administration of ApoG2 with gemcitabine resulted in a statistically higher antitumor activity compared with either ApoG2 or gemcitabine alone in a severe combined immunodeficiency mouse xenograft model. Conclusions: Apogossypolone, which functions as a potent pan-Bcl-2 family inhibitor, seems therapeutically promising for future translational studies including the treatment of pancreatic cancer.

Ipilimumab augments antitumor activity of bispecific antibody-armed T cells

BackgroundIpilimumab is an antagonistic monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that enhances antitumor immunity by inhibiting immunosuppressive activity of regulatory T cells (Treg). In this study, we investigated whether inhibiting Treg activity with ipilimumab during ex vivo T cell expansion could augment anti-CD3-driven T cell proliferation and enhance bispecific antibody (BiAb)-redirected antitumor cytotoxicity of activated T cells (ATC).MethodsPBMC from healthy individuals were stimulated with anti-CD3 monoclonal antibody with or without ipilimumab and expanded for 10-14 days. ATC were harvested and armed with anti-CD3 x anti-EGFR BiAb (EGFRBi) or anti-CD3 x anti-CD20 BiAb (CD20Bi) to test for redirected cytotoxicity against COLO356/FG pancreatic cancer cell line or Burkitt’s lymphoma cell line (Daudi).ResultsIn PBMC from healthy individuals, the addition of ipilimumab at the initiation of culture significantly enhanced T cell proliferation (pu2009=u20090.0029). ATC grown in the presence of ipilimumab showed significantly increased mean tumor-specific cytotoxicity at effector:target (E:T) ratio of 25:1 directed at COLO356/FG and Daudi by 37.71% (pu2009<u20090.0004) and 27.5% (pu2009<u20090.0004), respectively, and increased the secretion of chemokines (CCL2, CCL3, CCL4,CCL5, CXCL9, and granulocyte-macrophage colony stimulating factor(GM-CSF)) and cytokines (IFN-γ, IL-2R, IL-12, and IL-13), while reducing IL-10 secretion.ConclusionsExpansion of ATC in the presence of ipilimumab significantly improves not only the T cell proliferation but it also enhances cytokine secretion and the specific cytotoxicity of T cells armed with bispecific antibodies.

Nab-paclitaxel: potential for the treatment of advanced pancreatic cancer

Advanced pancreatic adenocarcinoma is a deadly disease and is considered incurable. For the past two decades, gemcitabine remained the major chemotherapeutic drug with modest clinical benefit. Many chemotherapy and targeted agents were combined with gemcitabine but failed to demonstrate improvement in pancreatic cancer (PC) survival. Taxanes (paclitaxel, docetaxel) were introduced in the clinic as anti-microtubule agents and showed activity against PC cells in vitro; however, clinical efficacy was limited. Nab-paclitaxel (Abraxane) is an albumin-bound paclitaxel that has shown clinical activity in advanced breast and lung cancer. Recently, nab-paclitaxel was tested in a large Phase III clinical trial in combination with gemcitabine for the treatment of advanced PC. The data showed that the addition of nab-paclitaxel improved the response rate (7% in gemcitabine alone versus 23% in combination), progression-free survival (from 3.7 months to 5.5 months), and overall survival from 6.7 months to 8.5 months, compared to single agent gemcitabine. Through this review, we provide the preclinical and clinical progress in the development of nab-paclitaxel for the treatment of metastatic PC.

Multi-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer

PURPOSEnGemcitabine (G) has been shown to sensitize pancreatic cancer to radiotherapy but requires lower doses of G and thus delays aggressive systemic treatment, potentially leading to distant failure. We initiated a phase I trial combining ultra-fractionated low-dose radiotherapy with full dose G and erlotinib in the treatment of patients with advanced pancreatic cancer.nnnMETHODSnPatients with locally advanced or metastatic pancreatic cancer confined to the abdomen and an ECOG performance status (PS) of 0-1 who had received 0-1 prior regimens (without G or E) and no prior radiotherapy were eligible. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4h on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD).nnnRESULTSn27 patients (median age 64 years and 15 male) were enrolled between 11/24/08 and 4/12/12. 1 patient withdrew consent prior to receiving any protocol therapy. 17 patients had a PS of 1. The majority of patients were stage IV. One DLT was noted out of 7 patients at dose level (DL) 1. Subsequently no DLTs were noted in 3 patients each enrolled at DL2-4 or 11 patients in the expansion cohort. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Best response in 24 evaluable patients: PR (8), stable (15), PD 1. Median survival for the entire group was 9.1 months.nnnCONCLUSIONnThis phase I study combining low-dose ultra-fractionated RT as a sensitizer to full dose G plus E was well tolerated with encouraging efficacy. This represents a novel strategy worthy of further investigation in advanced pancreatic cancer patients.

What Options Are Available for Refractory Pancreatic Cancer

Currently gemcitabine-based regimens and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) are widely used standard for first-line treatment of patients with advanced pancreatic adenocarcinoma. Refractory patients may receive either FOLFOX (5-fluorouracil and oxaliplatin) or gemcitabine based on the first line regimen. This review is an update from the 2012 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium regarding recent developments in the treatment of refractory pancreatic cancer, as these were presented in Abstracts #248 and #373 of the meeting.

Women at increased risk for cardiac toxicity following chemoradiation therapy for esophageal carcinoma

PURPOSEnThe purpose of this study was to identify factors associated with cardiac toxicity in patients treated with chemoradiation therapy (CRT) for esophageal carcinoma.nnnMETHODS AND MATERIALSnOne hundred twenty-seven patients with adenocarcinoma or squamous cell carcinoma of the esophagus treated from July 2002 to June 2011 at 2 academic institutions with preoperative or definitive CRT were retrospectively reviewed. Association of cardiac toxicity with a number of variables was investigated, including heart disease, cardiac bypass and angioplasty, diabetes, insulin use, smoking, chemotherapy regimen, and tumor location. T test assessed risk of cardiac toxicity secondary to age. Dose volume histograms (DVH) were evaluated for percentage of heart volume receiving >20, 30, 40, and 50 Gy (V20-V50). The Fisher exact test analyzed for an association between dose volume parameters and cardiac toxicity.nnnRESULTSnPatient population included 100 men and 27 women with a mean age of 64 years. Median follow-up was 12.7 months (range, 0.3-99.6 months). Any cardiac toxicity occurred in 28 patients, the majority of which were pericardial effusion (23/28). Odds ratio for toxicity in women was 4.15 (95% confidence interval [CI], 1.63-10.50; P = .0017) and time to cardiac toxicity by sex was significant (P = .0003). Patients above the median cutoff for V20, V30, and V40 had increased odds of developing cardiac toxicity (P = .03, .008, .002). There was 4.0 increased odds of developing cardiac toxicity with V40 >57% (95% CI, 1.5-10.3, P = .002). On multivariable logistic regression analysis, sex was the only variable associated with any cardiac toxicity and pericardial effusion (P = .0016, P = .0038). None of the other investigated variables were associated with increased risk of cardiac toxicity.nnnCONCLUSIONSnFemale patients and dose greater than the median for V20-V40 were associated with the development of cardiac toxicity, specifically pericardial effusion. These data suggest exercising increased care when designing radiation fields in women undergoing CRT for esophageal carcinoma, as pericardial effusion may be a long-term complication.

Is there a role for second line therapy in advanced pancreatic cancer

FOLFIRINOX (5-FU, oxaliplatin and irinotecan) and gemcitabine based regimens are widely used for the first-line treatment for patients with advanced pancreatic adenocarcinoma. Nab-paclitaxel and gemcitabine has replaced the use of many single agent gemcitabine in these patients population. In patients who progress on the first line therapy use of either 5-FU, leucovorin and oxaliplatin (FOLFOX) or gemcitabine and nab-paclitaxel combination has become a de facto standard depending on the chemotherapy they received in first line. Progress made in first line chemotherapy has lead to more interest in refractory pancreatic cancer. This article examines the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium regarding recent developments in the treatment of refractory pancreatic cancer, as these were presented in Abstracts #296, #297, #337, #344, and #381 of the meeting.

Retrospective review of cancer patients ≥80 years old treated with chemotherapy at a comprehensive cancer center

CONTEXTnThe percentage of cancer patients > or =80 years old is expected to increase in the next few years. However data on the use of chemotherapy in these patients are limited.nnnOBJECTIVEnWe conducted a retrospective review to define the profile of patients > or =80 years old who received chemotherapy at our center and assess their survival.nnnDESIGN, SETTING AND PARTICIPANTSnPatients > or =80 years treated with chemotherapy between 1 January 2000 and 31 December 2004 were included in this analysis.nnnRESULTSnOf the 4689 patients treated with chemotherapy over the 5-year period, 133 patients (3%) were > or =80 years old. The median age was 83 years. 61% were females and 39% were males. 16% had hematologic tumors and 84% had solid tumors. Gynecological (32%) and aerodigestive cancers (27%) were the most common sites and lung cancer (22%) was the most common cancer. During the first regimen, 512 cycles of chemotherapy were delivered with a median of 3 cycles (range: 1-24 cycles). 49% received single and 51% multidrug regimens. Carboplatin was the most common single agent and carboplatin and paclitaxel was the most common combination among solid tumor patients. 19% of solid tumor patients received radiation with chemotherapy. The 1-year survival among hematologic cancer and solid tumor patients was 65% and 48%, respectively. Stage of disease was the only statistically significant factor predicting survival.nnnCONCLUSIONSnIn cancer patients > or =80 years old selected for chemotherapy, both single and multi-agent therapy appeared to be feasible.

Biomarkers for Pancreatic Cancer: Is it Ready for Primetime?

Standard treatment for advanced pancreatic cancer has had minimal impact on natural course of the disease. Current standard chemotherapy for healthy, robust patients remains FOLFIRINOX (5fluorouracil, leucovorin, oxaliplatin, and irinotecan) chemotherapy which showed 4-month overall survival benefit compared to gemcitabine alone [2]. Recently MPACT study showed that adding nabpaclitaxel to gemcitabine significantly improved overall survival compared to gemcitabine (8.5 months vs. 6.7 months P=0.000015). However, the combination remains more toxic compared to gemcitabine [3].

Evidence-based Anticancer Materia Medica for Colorectal Cancer

Unfortunately, majority of patients with metastatic colorectal cancer cannot be cured. Current available systemic chemotherapy and targeted agents produce meaningful improvement in median survival and progression free survival. However toxicity associated with these therapies can worsen the quality of life for patients. Therefore there is an interest in looking at alternative medicine to reduce the side effect and possibly enhance the efficacy of cytotoxic chemotherapy. There are a large number of preclinical studies looking at ginseng products as chemopreventive agents. They induce apoptosis and cytotoxicity in multiple colorectal cell lines but lack of definitive clinical studies. Both curcumin and thymoquinone show promising preclinical data in vitro and in vivo but lack of clinical efficacy studies. There is emerging preclinical data that herbal products in combination with chemotherapy can reduce toxicity and enhance the cytotoxicity of chemotherapeutic agents like 5-fluorouracil. However there is discordance between the amount of preclinical data available and what herbal agents are tested in clinical trial setting. In this chapter, we will review the current data available for herbal medicine in the treatment of advanced colorectal cancer.