Faculty Bibliography

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect. Sixty-eight adults were randomized to take either ginger or placebo daily for 6 weeks, with a 6-week washout and longitudinal stool collection throughout. We performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of pre-specified CRC-associated taxa using mixed-effects logistic regression. Ginger supplementation showed no significant effect on microbial community structure through alpha or beta diversity. Of 10 pre-specified CRC-associated taxa, there were significant decreases in the relative abundances of the genera Akkermansia (p < 0.001), Bacteroides (p = 0.018), and Ruminococcus (p = 0.013) after 6-week treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances of Akkermansia and Bacteroides, which suggests that ginger may have an inhibitory effect on CRC-associated taxa. Overall, ginger supplementation appears to have a limited effect on gut microbiome in patients with colorectal adenomas.

Introduction: Gemcitabine and carboplatin/cisplatin ("platinum")-based combinations are used to treat a wide variety of malignancies including gynecologic, breast, lung, and occult primary cancers. In Non-Small Cell Lung Cancer (NSCLC), these combinations led to a substantial improvement in overall survival. Nevertheless, a large proportion of patients do not respond. An optimal cytotoxic strategy for managing NSCLC and the discovery of predictive biomarkers for cytotoxic chemotherapy to guide treatment selection remain unmet needs in the clinic. The Cellworks Computational Omics Biology Model (CBM) platform identified a unique chromosomal signature which permits a stratification of patients that are most likely to respond to gemcitabine and platinum treatments.
Method(s): Twenty patients treated with gemcitabine and platinum were identified from a TCGA dataset and analyzed. The mutation and copy number aberrations from individual cases served as input into the CBM to generate a patient-specific protein network map from PubMed and other online resources. Disease-biomarkers unique to each patient were identified within patient-specific protein network maps. Digital drug biosimulations were conducted by measuring the effect of gemcitabine and platinum on a cell growth score comprised of a composite of cell proliferation, viability, apoptosis, metastasis, and other cancer hallmarks. Drug biosimulations were conducted by mapping the drug combination to the patient genome along with a rational mechanism of action and validated based on the patient's genomic profile and biological consequences.
Result(s): Of the 20 patients treated with gemcitabine and platinum, 12 had clinical responses while 8 were non-responders. The CBM correctly predicted response in 17/20 patients with 85% accuracy, 63% specificity and 100% sensitivity. The CBM identified that novel amplified segments of Chromosome 6p were associated with non-responsiveness to gemcitabine and platinum therapy. Key genes on these segments include E2F3, MDC1, TAP1 and TNF. Amplification of E2F3 leads to activation of MSH2/6, which enhances mismatch repair thereby causing resistance. Amplification of MDC1 leads to activation of CHECK2, BRCA1, ATM, and NBN_RAD51_MRE1 Complex which stimulates homologous recombination repair. Amplification of TAP1 reduces gemcitabine transport. Besides 6p amplification, PRMT7 deletion was also associated with gemcitabine resistance. Notably, BRCA2-del, RB1-del, NPM1-del, LIG4-del, XRCC4-del, RAD50-del, ATRX-Del, RBBP8-del, XRCC6-del, and FBXW7-del were also prevalent among gemcitabine non-responders. Interestingly, these aberrations also happen to be key criteria for predicting response to etoposide. Therefore, etoposide and platinum combinations might have provided better disease control for these patients.
Conclusion(s): Amplification of chromosome 6p appears to be an important cause of treatment failure for patients receiving gemcitabine-platinum combinations. In this small patient group, the Cellworks CBM was especially useful for identifying non-responders. Biosimulation can identify novel patient subgroups for therapy response prediction and has promise to help select more effective therapies. Keywords: Multi-omics Therapy Biosimulation, Personalized Cancer Therapy, Cancer Therapy Biosimulation
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Introduction: Cytotoxic drugs are hampered by limited efficacy. Hence, a personalized treatment approach matching chemotherapy with appropriate patients remains an unmet need. Genomic heterogeneity creates an opportunity to discern key genomic aberrations and pathways that confer resistance and response to standard treatment options. We conducted a study using the Cellworks Computational Omics Biology Model (CBM) to identify novel genomic biomarkers associated with response among Non-Small Cell Lung Cancer (NSCLC) patients receiving platinum-based treatments.
Method(s): 104 NSCLC patients who received platinum-based chemotherapy were selected from TCGA: platinum-etoposide (N=18), platinum-gemcitabine (N=20), platinum-vinorelbine (N=31), platinum-paclitaxel (N=21), and platinum-docetaxel (N=14). Mutation and CNV from each case served as input for the CBM to generate a patient-specific protein network-map based on PubMed and other resources. Biomarkers unique to each patient were identified within protein network-maps. Drug impact on the disease network was biosimulated to determine efficacy score by measuring the effect of chemotherapy on the cell growth score, a composite of cell proliferation, viability, apoptosis, metastasis, DNA damage and other cancer hallmarks. Effectively, the mechanism of action of each drug was mapped to each patient's genome and biological consequences determined response.
Result(s): Among the 104 patients, 74 were responders (R) and 30 non-responders (NR), determined using compete and partial response based on RECIST criteria (Figure 1). The CBM predicted clinical response with 73% sensitivity and 77% specificity. Cellworks CBM identified novel biomarkers responsible for platinum-based combination therapy response as mentioned below. +Etoposide: 13q-del, RB1-del, MBD1-del, LIG4-del, ERCC5-del, ATP7B-del +Gemcitabine: AKT3-amp, MAPKAP2-amp, TAP1-del +Vinorelbine: TET2-del/LOF, TRIB3-amp, SLX4-del +Paclitaxel: KLF4-del, SNCG-del, RAC1-amp/GOF +Docetaxel: BCL2L1-amp, HMGA1-amp, NSD1-del, SLC22A7-amp, FSIP1-del These genes contributed to drug efficacy by impacting various pathways, including DNA repair, oxidative-stress, methylation machinery, spindle formation, and mitotic-catastrophe. The aberration frequency of these genes was high among the responders within each subgroup and was very low in non-responders. Additionally, a model of clinical outcome versus the linear and quadratic function of efficacy score, drug combination and the interaction of both showed that efficacy score provides predictive information above and beyond the choice of drug combination alone (likelihood ratio chi-sq = 35.56, df=13, p-value = 0.0007). [Formula presented]
Conclusion(s): This pilot study highlights how the Cellworks CBM biosimulation platform can help identify patients for therapy response prediction. By using novel biomarkers, a CBM-informed decision tree can be employed to identify the optimal drug combination for platinum-based therapy. We suggest that this approach be validated prospectively in a larger patient cohort. Keywords: Cancer Therapy Biosimulation, Multi-omics Therapy Biosimulation, Personalized Cancer Therapy
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Immunotherapy in the metastatic setting has drastically altered the landscape of treatment for various types of malignancy, including colorectal cancer. The category of immune checkpoint inhibitors has especially emerged as a class of therapy predicated on a more comprehensive understanding of immune cell-cancer cell regulation and evolution of the tumor microenvironment over time. Strategies including adoptive cellular therapies, tumor vaccines, and antibodies have also demonstrated the ability to enhance antitumor immunity. In this article, we provide a comprehensive review of the current landscape of immunotherapeutic strategies in colorectal cancer and provide insight into how these strategies may evolve in the next decade and be adapted to more localized forms of cancers of the colon and rectum. We provide particular focus on various combination approaches under investigation for reversing cancer-induced immunosuppression, especially in mismatch repair-proficient/microsatellite-stable colorectal tumors. Finally, we summarize current understanding on a recently identified integral factor in local immune regulation, the colonic microbiome. The aim of this article is to identify current challenges and barriers to improvement and to specify opportunities for applying knowledge in the immunotherapy sphere to rational design of clinical trials intended to improve survival and related outcomes in patients treated in the neoadjuvant setting.

BACKGROUND:Increasing evidence suggests that tobacco smoking, a well-known driver of carcinogenesis, influences the gut microbiome; however, these relationships remain understudied in diverse populations. Thus, we performed an analysis of smoking and the gut microbiome in a subset of 803 adults from the multi-ethnic NYU FAMiLI study. METHODS:We assessed fecal microbiota using 16S rRNA gene sequencing, and clustered samples into Amplicon Sequence Variants using QIIME2. We evaluated inferred microbial pathway abundance using PICRUSt. We compared population beta diversity, and relative taxonomic and functional pathway abundance, between never smokers, former smokers, and current smokers. RESULTS:We found that the overall composition of the fecal microbiome in former and current smokers differs significantly from that of never smokers. The taxa Prevotella and Veillonellaceae were enriched in current and former smokers, while the taxa Lachnospira and Tenericutes were depleted, relative to never smokers. These shifts were consistent across racial and ethnic subgroups. Relative to never smokers, the abundance of taxa enriched in current smokers were positively correlated with the imputed abundance of pathways involving smoking-associated toxin breakdown and response to reactive oxygen species (ROS). CONCLUSIONS:Our findings suggest common mechanisms of smoking associated microbial change across racial subgroups, regardless of initial microbiome composition. The correlation of these differentials with ROS exposure pathways may suggest a role for these taxa in the known association between smoking, ROS and carcinogenesis. IMPACT/CONCLUSIONS:Smoking shifts in the microbiome may be independent of initial composition, stimulating further studies on the microbiome in carcinogenesis and cancer prevention.

The activity of T cell mediated immunotherapies in B cell lymphoma has been limited to date. The novel bi-specific antibody CD20-TCB, has a 2:1 antibody design to maximize T cell engagement, and demonstrates activity in preclinical models. This may represent a novel therapeutic approach for patients with relapsed/refractory NHL.

Hairy cell leukemia (HCL) and Merkel cell carcinoma (MCC) are two rare malignancies with distinct cells of origin. HCL is a lymphoid malignancy of mature B cells, and MCC derives from neuroendocrine cell origin. HCL has a favorable prognosis with most patients achieving long-term remission and potential cure. In contrast, MCC is an aggressive malignancy affecting the skin and can metastasize quickly with a dismal prognosis. Immunocompromised patients, such as those with AIDS, posttransplant, and the elderly, have higher incidences than the general population, suggesting a possible immune mechanism. We report a case where a patient presented with HCL and metastatic MCC synchronously. This is the first reported case of these two rare malignancies occurring concurrently at initial presentation and may represent a role of immunosuppression in the pathogenesis of MCC.