SPOREs
Gastrointestinal Cancers
Projects
Projects
Project 1: Improved staging of pancreatic cancer
Co-Principal Investigators: Ralph Weissleder, MD, PhD (MGH) and Andrew Warshaw, MD (MGH)
Pancreatic adenocarcinoma is a deadly disease with few effective therapeutic options. Surgical resection of early stage disease offers the only possibility of long-term survival. The overall care of patients with localized pancreatic cancers would be greatly aided by methods that accurately predict the clinical course of patients considered for surgery. In this way, extensive surgery could be avoided in those unlikely to benefit, and these patients can instead be considered for supportive care or experimental therapies.
We propose to improve the pre-operative staging of patients with localized pancreatic cancers using novel imaging tools. This project describes a clinical protocol to determine whether magnetic resonance imaging with lymphotropic superparamagneticnanoparticals (LN-MRI) will accurately predict the presences of lymph node metastases in patients with pancreatic cancer. In addition, each patient will have state-of-the-art imaging measuring other tumor parameters such as tumor volume (CE-MDCT), microvascularity (VVF-MRI) and glycolysis (PET-CT). Outcome data at 3 years post-surgery will be collected an all study participants. Tumor specimens obtained at the time of surgery will be analyzed using gene expression microarrays to identify candidate biomarkers for the development of novel imaging targets for PaNIN and PDAC.
In addition to establishing new criteria for disease progression and survival, the data collected in these studies will provide valuable information necessary to develop new generations of novel diagnostics and potentially therapeutic agents for pancreatic cancer treatment.
Project 2: Molecular fluorescent imaging for the early detection of colorectal neoplasia
Co-Principal Investigators: Raju Kucherlapati, PhD (HMS), Umar Mahmood, MD, PhD (MGH), Daniel Chung, MD (MGH), and Andrew Chan, MD, MPH (MGH)
When colorectal cancer (CRC) is detected at an early stage, the 5-year survival exceeds 95%. Although colonoscopy is an excellent screening tool and considered the current gold standard, there is a miss rate for polyps as high as 22%. In particular, “Flat lesions” in the colon are more commonly missed and may be more likely to contain areas of dysplasia. The problem is further exacerbated in ulcerative colitis (UC), in which dysplasia can develop in macroscopically normal-appearing mucosa. Thus, there is a need to develop novel technologies that would permit the early detection and in situ characterization of early neoplastic colonic lesions with high sensitivity and specificity.
The overall goal of this proposal is to clinically translate novel imaging agents and devices we have developed to address this unmet need. Specifically, we will utilize a class of “smart” agents that increase their near infrared (NIR) fluorescence after selective interaction with a target protease (cathepsin) that is overexpressed in colonic adenomas and adenocarcinomas. Utilizing this technology, our preliminary studies have demonstrated superior endoscopic detection or preneoplastic lesions in mouse models of colon cancer when compared to conventional white light examinations. Moreover, we have observed comparable sensitivity and specificity of this technique for neoplasia that arises in the background of chronic UC. We seek to optimize and characterize this agent in new mouse models that spontaneously develop focal colonic adenomas and adenocarcinomas of known age and location. Cathepsin protease expression will be correlated with lesion progression in these mouse models as well as in a broad spectrum of ex vivo human neoplastic lesions.
The culmination of this effort will be a pilot clinical trial in which the feasibility of diagnostic performance of this novel technology will be evaluated in patients with sporadic invasive CRC, patients with polyposis syndromes, and patients with dysplasia in the setting of UC.
Project 3: Defining optimal doses of vitamin D for chemoprevention in Blacks
Co-Principal Investigators: Edward Giovannucci, MD, ScD (HSPH), Karen Emmons, PhD (DFCI), Gary Bennett, PhD (DFCI), and Charles Fuchs, MD, MPH (DFCI)
An increasing body of evidence suggests that vitamin D may reduce the risk of colorectal cancer and other cancers of the digestive system, acting through various proposed methods, including a reduction of pro-inflammatory factors. Blacks and African-Americans have virtually half the levels of 25(OH)D, the generally accepted best indicator of vitamin D status, compared to Whites. Differences in levels of plasma 25(OH)D could account for the greater incidence of colorectal cancer and other digestive system cancers in Blacks, particularly in the northeastern U.S., where solar UV-B intensity is low. The optimal dose of supplemental vitamin D needed to achieve adequate levels of plasma 25(OH)D is unknown, but it is likely to be much higher than currently recommended doses (400 IU/day). A critical need exists, particularly in Blacks, to define doses of oral vitamin D supplement that will achieve a sufficient level of plasma 25(OH)D before vitamin D chemoprevention studies are initiated. We therefore propose to examine plasma 25(OH)D in an underserved population of Blacks living in the Boston area and establish a dose of vitamin D supplementation that will achieve a presumed protective level of plasma 25(OH)D levels in this cohort.
First, following assessment of baseline plasma 25(OH)D levels, 320 participants will be randomized to placebo, 1000 IU, 2000 IU, or 4000 IU of vitamin D3 (cholecalciferol) per day in a 1:1:1:1 ratio. Then, after 3 months of supplementation, plasma levels of 25(OH)D will be determined. Secondly, we will examine if oral vitamin D supplementation reduces plasma levels of pro-inflammatory factors C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-R2 (TNFR2), and increases anti-inflammatory interleukin-10 (IL-10) levels. Thirdly, participants will be genotyped for relevant vitamin D pathway genes, and genotype prevalence will be compared to results from participants for the Nurses’ Health Study and Health Professionals Follow-up Study, two cohorts for which we are separately funded to examine the influence of these genotypes on the risk of colorectal adenoma and cancer. We will also compare baseline 25(OH)D levels with Whites of these cohort members living in a similar latitude and who provided blood in the same season. We will also assess rise of 25(OH)D according to 25(OH)D-24-hydroxylase (CYP24) genotypes, as genetic variation in CYP24 as been proposed to contribute to lower 25(OH)D in blacks.
Results of this trial will help direct future randomized trials of vitamin D in the prevention of colorectal neoplasia and other cancers of the digestive system. In fact, once we define the optimal dose of vitamin D, our interdisciplinary team with expertise in disparities will be well positioned to lead an intervention trial that has major implications for efforts to address colorectal neoplasia disparities nationally.
Project 4: The role of PI3-Kinase signaling pathway in defining sensitivity and resistance to anti-EGFR therapy in colorectal cancer
Co-Principal Investigators: Lewis Cantley, PhD (BIDMC), Jeffrey Engelman, MD, PhD (MGH), Jeffrey Meyerhardt, MD, MPH (DFCI), and David Ryan, MD (MGH)
Clinical studies indicate that a humanized monoclonal antibody against the Epidermal Growth Factor Receptor (EGFR), cetuximab, confers an objective tumor response in a subset of patients with metastatic colorectal cancer. However, most patients do not respond to cetuximab and therefore receive limited or no benefit from this drug. Currently, there is no test that can predict if a cancer will respond to cetuximab. Compelling evidence supports the view that targeting the receptor tyrosine kinases (RTK), particularly those that engage the Phosphoinositide 3-Kinase (PI3K) signaling pathways, is a highly effective strategy for killing for cancers.
Accordingly, the therapeutic response to anti-RTK therapy has been shown to be modulated dramatically by the mutational status of key signaling components in the PI3K pathway. The PI3K/Akt signaling pathway drives many epithelial cancers, and its importance is colorectal cancers is underscored by the presence of PIK3CA mutations (the gene encoding for PI3K) in 20-30% of these cancers. PI3K can be activated by multiple different signaling pathways including EGFR, and there is accumulating evidence that EGFR regulates PI3K via distinct mechanisms in cancers sensitive to anti-EGFR therapies.
We propose to study the PI3K signaling pathway, biochemically and genetically, in colorectal cancers with the translational goal of identifying markers that will predict sensitivity to cetuximab. This will enable the selection of patients that are most likely to benefit from cetuximab. Additionally, these studies may also reveal additional therapeutic targets to enhance cetuximab sensitivity. Our specific aims include: (1) Identify the mechanisms for activating the PI3K/AKT pathway in colorectal cancers; (2) To determine the differences in PI3K regulation between cetuximab sensitive and resistant colorectal cancers in xenograft tumor models; (3) To determine if we can use the information discovered in the first two aims to identify markers that will predict which colorectal cancers will respond to cetuximab.
Project 5: Targeted therapy resistance mechanisms in gastrointestinal stromal tumor (GIST)
Co-Principal Investigators: Jonathan Fletcher, MD (BWH) and George Demetri, MD (DFCI)
This project focuses on characterizing targeting therapy resistance mechanisms in gastrointestinal stromal tumors (GISTs). Most GISTs express mutant, constitutively activated, KIT or PDGFRA oncoproteins. We have shown that these formerly untreatable cancers can be palliated in 80% of patients by oral single-agent therapy with eh KIT/PDGFRA inhibitor, imatinib. Patients who develop resistance to imatinib can benefit from second-line therapy with sunitinib, which is an alternative KIT/PDGFRA inhibitor. Ultimately, however, most GIST patients will progress on both of these FDA-approved kinase inhibitors. Therefore, the aims of the research proposed here are to characterize imatinib/sunitinib resistance mechanisms.
Our preliminary studies show that GIST imatinib resistance mechanisms vary from patient to patient, and also between metastatic lesions in a given patient. We have shown that even a single progressing GIST metastasis contains subsets of cells whose imatinib resistance mechanism differs from those in other cells from the same tumor focus. In the present effort, by revealing the scope – and particularly the heterogeneity – of the imatinib/sunitinib resistance problem in GIST we will provide the understanding needed to design more effective clinical strategies. At the same time, these studies will enable the development of biomarkers, assays and cell lines to enable preclinical validation of novel therapeutic strategies to circumvent imatinib/sunitinib resistance into improved medical therapy for GIST patients who are progressing on imatinib or sunitinib.
Initially, we will evaluate HSP90 inhibition as a strategy to inhibit the varied gain-of-function KIT mutations that manifest, in each patient, at the point of clinical progression on imatinib and sunitinib. This will be accomplished through a phase I/II clinical trial of the HSP90 inhibitor, IPI-504, combined with imatinib, in patients showing progression of metastatic GIST on imatinib or sunitinib. Through these studies, we will translate the basic science proposed in this SPORE through clinical application.
