Bilal Piperdi

Human Barrett's adenocarcinoma of the esophagus, associated myofibroblasts, and endothelium can arise from bone marrow-derived cells after allogeneic stem cell transplant.

This study characterizes the contribution of bone marrow-derived cells (BMDCs) to Barretts adenocarcinoma of the esophagus using a mouse surgical model of disease and human specimens. Transplantation of bone marrow expressing beta galactosidase into a wild-type mouse, followed by surgical esophagojejunostomy, allowed tracking of BMDCs into the surgical anastomosis and resulting Barretts metaplasia. Human tissue from a male patient who had been transplanted with female bone marrow and later developed esophageal adenocarcinoma allowed us to tract donor-derived cells into the tumor. Using a combination of antibodies directed against beta-galactosidase (animal studies) and X/Y fluorescent in situ hybridization (FISH) (human studies), combined with specific lineage staining directed against epithelial, fibroblast, endothelial, and leukocyte markers, we show that bone marrow cells contribute to both the epithelial and stromal component of esophageal adenocarcinoma. These findings demonstrate that BMDCs can generate cancer-associated fibroblasts as well as contribute directly to epithelial cells in cancer of the esophagus.

The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib

Introduction: The epidermal growth factor receptor (EGFR) inhibitor erlotinib is much less effective in non–small-cell lung cancer (NSCLC) tumors with wild-type EGFR, than in tumors with activating EGFR mutations. Autophagy is a tightly regulated lysosomal self-digestion process, which may alternatively promote cell survival or type II cell death. This study assessed the role of autophagy in erlotinib-mediated cytotoxicity. Methods: We used wild-type EGFR erlotinib-sensitive and erlotinib-resistant NSCLC cell lines to determine whether inhibiting autophagy by a therapeutic agent potentiated the antitumor activity of erlotinib in vitro and in vivo. Results: Erlotinib at a clinically relevant concentration (2 &mgr;M) induced autophagy in NSCLC cells with wild-type EGFR, and the degree of induction was greater in cells that were resistant than sensitive, suggesting that autophagy is cytoprotective. This was confirmed by knockdown of the autophagy-related gene Atg-5, and by using the autophagy inhibitor chloroquine (CQ), both of which increased the cytotoxicity of erlotinib. The synergistic activity of CQ was not because of the potentiation of erlotinib’s effects on autophagy, cell-cycle arrest, and inhibition of both EGFR or downstream signaling of EGFR. Rather, CQ markedly activated apoptosis in the cells. The ability of CQ to potentiate the antitumor activity of erlotinib was also seen in mice bearing NSCLC tumor xenografts. Conclusions: The ability to adapt to anti-EGFR therapy by triggering autophagy may be a key determinant for resistance to erlotinib in wild-type EGFR NSCLC. Inhibition of autophagy by CQ represents a novel strategy to broaden the spectrum of erlotinib efficacy in wild-type EGFR NSCLC tumors.

Bortezomib: Understanding the Mechanism of Action

Commentary on: nn[Yi-He Ling, Leonard Liebes, Bruce Ng, Michael Buckley, Peter J. Elliott, Julian Adams, Jian-Dong Jiang, Franco M. Muggia, and Roman Perez-Soler. PS-341, a Novel Proteasome Inhibitor, Induces Bcl-2 Phosphorylation and Cleavage in Association with G2–M Phase Arrest and Apoptosis .

RICTOR amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors

UNLABELLEDnWe identified amplification of RICTOR, a key component of the mTOR complex 2 (mTORC2), as the sole actionable genomic alteration in an 18-year-old never-smoker with lung adenocarcinoma. Amplification of RICTOR occurs in 13% of lung cancers (1,016 cases) in The Cancer Genome Atlas and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling. In the latter series, 11% of cases harbored RICTOR amplification as the only relevant genomic alteration. Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the transforming capacity of RICTOR in a Ba/F3-cell system. The mTORC1/2 inhibitors were significantly more active against RICTOR-amplified lung cancer cells as compared with other agents targeting the PI3K-AKT-mTOR pathway. Moreover, an association between RICTOR amplification and sensitivities to mTORC1/2 inhibitors was observed. The index patient has been treated with mTORC1/2 inhibitors that led to tumor stabilization for more than 18 months.nnnSIGNIFICANCEnRICTOR amplification may define a novel and unique molecular subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors.

Dermatologic Toxicities from Monoclonal Antibodies and Tyrosine Kinase Inhibitors against EGFR: Pathophysiology and Management

Epidermal growth factor receptor (EGFR) inhibition has now been well established as an effective treatment for various cancers. The EGFR belongs to the ErbB family of tyrosine kinase receptors which regulate tumor cell differentiation, survival and proliferation. Activation of EGFR drives tumorigenesis in lung, head and neck, colorectal and pancreatic cancers. Irrespective of the type of cancer being treated and the mechanism by which tumor EGFR drives tumorigenesis, the major side effect of EGFR inhibition is a papulopustular (also described as maculopapular or acneiform) rash which occurs in about two thirds of treated patients. Interestingly, this rash has been commonly correlated with better clinical outcomes (objective tumor response and patient survival). The pathophysiology of dermatological toxicity from EGFR inhibitors is an important area of clinical research, and the proper management of the rash is essential to increase the therapeutic index from this class of drugs. In this paper, we review the dermatologic toxicities associated with EGFR inhibitors with an emphasis on its pathophysiology and clinical management.

Schedule-dependent interaction between the proteosome inhibitor bortezomib and the EGFR-TK inhibitor erlotinib in human non-small cell lung cancer cell lines

Introduction: Both erlotinib (E) and bortezomib (B) have shown single-agent activity in patients with non-small cell lung cancer. We studied the combination of these two novel biologic agents in vitro using a panel of non-small cell lung cancer cell lines. Methods: The growth inhibitory effect of E and B were determined by MTT assay on seven non-small cell lung cancer cell lines. The data obtained from the growth inhibition assay in response to the combination of E and B were subject to isobologram analysis. The effects of each individual drug as well as combination in different sequences on cell cycle and apoptosis were determined by flow cytometry. Results: Two of seven cell lines are sensitive to E. However, B has narrower range of cytotoxicity. The combination is neither synergistic nor additive in two of four cell lines tested. In H358 bronchoalveolar cell lines, the combination is more active than either agent alone. E causes G1 cell cycle arrest and B causes G2/M cell cycle arrest. In sequential studies, 24-hour previous exposure to E causes G1 arrest and abrogates the cytotoxic effect of B. This is observed in both E-sensitive as well as E-resistant cells and is accompanied by an increase in cell survival and a decrease in apoptosis. Conclusions: The combination of E and B is neither additive nor synergistic in two of four cell lines tested. In H358 bronchoalveolar cell, the combination is more active than either agent alone. The schedule-dependent antagonistic effect of E pre-exposure was observed. E pre-exposure causes G1 cell cycle arrest and abrogates the activity of B. Further in vivo studies of this combination are warranted.

A neoadjuvant strategy for pancreatic adenocarcinoma increases the likelihood of receiving all components of care: lessons from a single-institution database

BACKGROUNDnRecent studies have shown adjuvant therapy improves outcomes from pancreatic cancer (PC). This study investigates receipt and timing of PC treatments, and association with outcomes.nnnMETHODSnThe analysis cohort consisted of patients with newly-diagnosed PC at a single institution over 5 years. Primary Endpoints were (i) receipt of recommended therapy, and (ii) overall survival (OS).nnnRESULTSnAmong 102 patients, 52 underwent resection. Out of 36 localized resected and 16 locally advanced resected (LAR) patients, 26 and 13, respectively, received adjuvant therapy. Six of the latter group received neoadjuvant therapy. Median OS for resected patients was 15.7 months (range 0.6-51.4), compared with 7.7 for unresected patients (range 0.4-32.0) (P < 0.001), and 14.0 months for patients with resection alone (range 0.6-24.4) vs. 16.1 for patients who also received adjuvant therapy (range 3.2-51.4) (P= 0.027). Out of 46 patients undergoing up-front resection, 33 had R0 surgical margins. For the six LAR patients undergoing neoadjuvant therapy, all margins were R0.nnnCONCLUSIONnAfter resection, a substantial proportion of patients do not receive adjuvant therapy, and have worse survival. In this study, neoadjuvant treatment increased both the proportion of patients receiving all components of recommended therapy and the R0 resection rate.

A national propensity-adjusted analysis of adjuvant radiotherapy in the treatment of resected pancreatic adenocarcinoma

The benefit of adjuvant radiotherapy (RT) for resected pancreatic adenocarcinoma remains controversial after randomized clinical trials. In this national‐level US study, a propensity score (conditional probability of receiving RT) was used to adjust for potential confounding in nonrandomized designs from treatment group differences.

Coronary vasospasm with myocardial stunning in a patient with colon cancer receiving adjuvant chemotherapy with FOLFOX regimen.

Colorectal cancer (CRC) represents a major public health problem accounting for > 1 million cases of new cancers and about half a million deaths worldwide. The risk of recurrence remains high despite curative surgery in early disease stages. The incremental benefit in absolute recurrence-free survival from 5-fluorouracil (5-FU)-based regimens in young patients with high-risk colon cancer is not insignificant. We present a case of a 57-year-old otherwise healthy white man who was treated with adjuvant chemotherapy consisting of modified 5-FU/leucovorin/oxaliplatin (FOLFOX6) regimen for stage III colon cancer. He experienced significant cardiotoxicity related to infusional 5-FU. Because of his young age and high-risk cancer, the patient opted to continue with adjuvant bolus 5-FU-containing chemotherapy after a lengthy discussion. With close cardiac monitoring and treatment with calcium channel blocker to prevent coronary vasospasm, he was able to successfully complete adjuvant chemotherapy. Currently, there are no guidelines for predicting a patients risk for 5-FU-induced cardiotoxicity. Similarly, there is no uniform management of this 5-FU-related induced cardiotoxicity. We believe that our case report, with a brief review of related literature, might help fill some of this vacuum.

Phase-I/II study of bortezomib in combination with carboplatin and bevacizumab as first-line therapy in patients with advanced non-small-cell lung cancer.

Background: This study aimed to establish the maximum tolerated dose (MTD) of weekly bortezomib in combination with fixed standard doses of carboplatin and bevacizumab, and to estimate the efficacy (response rate and progression free survival [PFS]) and safety of combination therapy with carboplatin, bortezomib, and bevacizumab as first-line therapy in patients with advanced non–small-cell lung cancer (NSCLC). Methods: Patients were assigned to three dose levels of weekly bortezomib with the fixed standard doses of carboplatin AUC 6 and bevacizumab (15 mg/kg) every 3 weeks using a standard phase-I design. Bortezomib doses were 1.3 mg/m2, 1.6 mg/m2, and 1.8 mg/m2 weekly on day 1 and day 8 of every 3-week cycle. A maximum of six cycles was administered. Patients with complete, partial response or stable disease were continued on single-agent bevacizumab (15 mg/kg every 3 weeks) as maintenance therapy. In phase II, either level III or MTD was administered to evaluate the efficacy and safety of the combination in first-line treatment of advanced NSCLC. Results: Sixteen patients were enrolled (three, four, and nine patients in dose level I, II, and III, respectively). There was no predefined dose limiting toxicity in cycle 1 in all 16 patients. The recommended phase-II dose is bortezomib 1.8 mg/m2 weekly on day 1 and day 8 in combination with carboplatin AUC 6 and bevacizumab 15 mg/kg on every 21-day cycle. Totally 9 patients were treated at the recommended phase-II dose level. The most common treatment related grade-3/4 toxicities during the subsequent cycles were thrombocytopenia (58%), lymphopenia (25%), neutropenia (12%), and diarrhea (25%). The grade-1/2 neuropathy was seen in 7 out of 16 patients (44%). The response rate, PFS, and overall survival in all patients were 37.5% (95%CI 13.8%–61.2%), 5.0 months (95%CI: 3.1–8.4), 9.9 months (95% CI: 8.2–14.1), and among the 9 patients in phase-II portion are 44% (95%CI 15.3%–77.3%), 5.5 months (95%CI: 3.1–2.2) and 10.9 months (95%CI: 8.0–14.1). Conclusion: The recommended phase-II dose for this combination is: carboplatin AUC 6, bevacizumab 15 mg/kg on day 1 and bortezomib 1.8 mg/m2 on day 1 and day 8 on every 21-day cycle. The regimen was very well tolerated with interesting clinical activity in first-line treatment of NSCLC.