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A pan-cancer organoid platform for precision medicine

Larsen, Brian M; Kannan, Madhavi; Langer, Lee F; Leibowitz, Benjamin D; Bentaieb, Aicha; Cancino, Andrea; Dolgalev, Igor; Drummond, Bridgette E; Dry, Jonathan R; Ho, Chi-Sing; Khullar, Gaurav; Krantz, Benjamin A; Mapes, Brandon; McKinnon, Kelly E; Metti, Jessica; Perera, Jason F; Rand, Tim A; Sanchez-Freire, Veronica; Shaxted, Jenna M; Stein, Michelle M; Streit, Michael A; Tan, Yi-Hung Carol; Zhang, Yilin; Zhao, Ende; Venkataraman, Jagadish; Stumpe, Martin C; Borgia, Jeffrey A; Masood, Ashiq; Catenacci, Daniel V T; Mathews, Jeremy V; Gursel, Demirkan B; Wei, Jian-Jun; Welling, Theodore H; Simeone, Diane M; White, Kevin P; Khan, Aly A; Igartua, Catherine; Salahudeen, Ameen A
Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.
PMID: 34320344
ISSN: 2211-1247
CID: 4949752

Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS

Rose Brannon, A; Jayakumaran, Gowtham; Diosdado, Monica; Patel, Juber; Razumova, Anna; Hu, Yu; Meng, Fanli; Haque, Mohammad; Sadowska, Justyna; Murphy, Brian J; Baldi, Tessara; Johnson, Ian; Ptashkin, Ryan; Hasan, Maysun; Srinivasan, Preethi; Rema, Anoop Balakrishnan; Rijo, Ivelise; Agarunov, Aaron; Won, Helen; Perera, Dilmi; Brown, David N; Samoila, Aliaksandra; Jing, Xiaohong; Gedvilaite, Erika; Yang, Julie L; Stephens, Dennis P; Dix, Jenna-Marie; DeGroat, Nicole; Nafa, Khedoudja; Syed, Aijazuddin; Li, Alan; Lebow, Emily S; Bowman, Anita S; Ferguson, Donna C; Liu, Ying; Mata, Douglas A; Sharma, Rohit; Yang, Soo-Ryum; Bale, Tejus; Benhamida, Jamal K; Chang, Jason C; Dogan, Snjezana; Hameed, Meera R; Hechtman, Jaclyn F; Moung, Christine; Ross, Dara S; Vakiani, Efsevia; Vanderbilt, Chad M; Yao, JinJuan; Razavi, Pedram; Smyth, Lillian M; Chandarlapaty, Sarat; Iyer, Gopa; Abida, Wassim; Harding, James J; Krantz, Benjamin; O'Reilly, Eileen; Yu, Helena A; Li, Bob T; Rudin, Charles M; Diaz, Luis; Solit, David B; Arcila, Maria E; Ladanyi, Marc; Loomis, Brian; Tsui, Dana; Berger, Michael F; Zehir, Ahmet; Benayed, Ryma
Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.
PMID: 34145282
ISSN: 2041-1723
CID: 4951402

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

Hoshino, Ayuko; Kim, Han Sang; Bojmar, Linda; Gyan, Kofi Ennu; Cioffi, Michele; Hernandez, Jonathan; Zambirinis, Constantinos P; Rodrigues, Gonçalo; Molina, Henrik; Heissel, Søren; Mark, Milica Tesic; Steiner, Loïc; Benito-Martin, Alberto; Lucotti, Serena; Di Giannatale, Angela; Offer, Katharine; Nakajima, Miho; Williams, Caitlin; Nogués, Laura; Pelissier Vatter, Fanny A; Hashimoto, Ayako; Davies, Alexander E; Freitas, Daniela; Kenific, Candia M; Ararso, Yonathan; Buehring, Weston; Lauritzen, Pernille; Ogitani, Yusuke; Sugiura, Kei; Takahashi, Naoko; Alečković, Maša; Bailey, Kayleen A; Jolissant, Joshua S; Wang, Huajuan; Harris, Ashton; Schaeffer, L Miles; García-Santos, Guillermo; Posner, Zoe; Balachandran, Vinod P; Khakoo, Yasmin; Raju, G Praveen; Scherz, Avigdor; Sagi, Irit; Scherz-Shouval, Ruth; Yarden, Yosef; Oren, Moshe; Malladi, Mahathi; Petriccione, Mary; De Braganca, Kevin C; Donzelli, Maria; Fischer, Cheryl; Vitolano, Stephanie; Wright, Geraldine P; Ganshaw, Lee; Marrano, Mariel; Ahmed, Amina; DeStefano, Joe; Danzer, Enrico; Roehrl, Michael H A; Lacayo, Norman J; Vincent, Theresa C; Weiser, Martin R; Brady, Mary S; Meyers, Paul A; Wexler, Leonard H; Ambati, Srikanth R; Chou, Alexander J; Slotkin, Emily K; Modak, Shakeel; Roberts, Stephen S; Basu, Ellen M; Diolaiti, Daniel; Krantz, Benjamin A; Cardoso, Fatima; Simpson, Amber L; Berger, Michael; Rudin, Charles M; Simeone, Diane M; Jain, Maneesh; Ghajar, Cyrus M; Batra, Surinder K; Stanger, Ben Z; Bui, Jack; Brown, Kristy A; Rajasekhar, Vinagolu K; Healey, John H; de Sousa, Maria; Kramer, Kim; Sheth, Sujit; Baisch, Jeanine; Pascual, Virginia; Heaton, Todd E; La Quaglia, Michael P; Pisapia, David J; Schwartz, Robert; Zhang, Haiying; Liu, Yuan; Shukla, Arti; Blavier, Laurence; DeClerck, Yves A; LaBarge, Mark; Bissell, Mina J; Caffrey, Thomas C; Grandgenett, Paul M; Hollingsworth, Michael A; Bromberg, Jacqueline; Costa-Silva, Bruno; Peinado, Hector; Kang, Yibin; Garcia, Benjamin A; O'Reilly, Eileen M; Kelsen, David; Trippett, Tanya M; Jones, David R; Matei, Irina R; Jarnagin, William R; Lyden, David
There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
PMID: 32795414
ISSN: 1097-4172
CID: 4565512

Biomarker-Based Therapy in Pancreatic Ductal Adenocarcinoma: An Emerging Reality?

Krantz, Benjamin A; O'Reilly, Eileen M
Over the last decade, many of the major solid organ cancers have seen improvements in survival due to development of novel therapeutics and corresponding biomarkers that predict treatment efficacy or resistance. In contrast, favorable outcomes remain challenging in pancreatic ductal adenocarcinoma (PDAC), in part related to the lack of validated biomarkers for patient and treatment selection and thus optimal clinical decision-making. Increasingly, however, therapeutic development for PDAC is accompanied by bioassays to evaluate response and to study mechanism of actions with a corresponding increase in the number of trials in mid to late stage with integrated biomarkers. In addition, blood-based biomarkers that provide a measure of disease activity and allow for minimally invasive tumor analyses are emerging, including circulating tumor DNA, exosomes, and circulating tumor cells. In this article, we review potential biomarkers for currently approved therapies as well as emerging biomarkers for therapeutics under development. Clin Cancer Res; 24(10); 2241-50. ©2017 AACR.
PMID: 29269376
ISSN: 1557-3265
CID: 4951392

Pancreas adenocarcinoma: novel therapeutics

Krantz, Benjamin A; Yu, Kenneth H; O'Reilly, Eileen M
Pancreatic ductal adenocarcinoma (PDAC) is the third highest cause of cancer-related deaths in the US, and is projected to be second only to non-small cell lung cancer (NSCLC) by the 2020s. Current therapies have a modest impact on survival and median overall survival (mOS) across all stages of disease remains under a year. Over the last decade, however, great strides have been made in the understanding of PDAC pathobiology including the role of the tumor microenvironment (TME), DNA damage repair and mechanism of immunosuppression. Exciting novel therapeutics are in clinical development targeting the TME to increase cytotoxic drug delivery, decrease immunosuppressive cell presence and attack cancer stem cells (CSCs). Immune checkpoint inhibitors, cancer vaccines and other immunotherapies are actively being studied and novel combinations of targeted agents are being pursued. There is a sense of optimism in the oncology community that these scientific advances will translate into improved outcomes for patients with PDAC in the proximate future. In this review, we examine various novel therapeutics under clinical development with a focus on stromal disrupting agents, immunotherapeutics and DNA damage repair strategies.
PMID: 28705007
ISSN: 2304-3873
CID: 4951382

Uveal melanoma: epidemiology, etiology, and treatment of primary disease

Krantz, Benjamin A; Dave, Nikita; Komatsubara, Kimberly M; Marr, Brian P; Carvajal, Richard D
Uveal melanoma (UM) is the most common intraocular malignancy and arises from melanocytes in the iris, ciliary body, or choroid. Early diagnosis and local treatment is crucial, as survival correlates with primary tumor size. However, approximately 50% of patients will develop metastatic disease with 6-12 months' survival from metastatic diagnosis. Genomic analyses have led to the development of gene-expression profiles that effectively predict metastatic progression; unfortunately, no adjuvant therapy has been shown to prolong survival to date. New insights into the molecular biology of UM have found frequent activating mutations in genes encoding for the G-protein α-subunit, GNAQ and GNA11, and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease. Studies are under way with rationally developed regimens targeting these pathways, and novel agents are under development. We review the diagnosis, management, and surveillance of primary UM and the adjuvant therapy trials under way.
PMID: 28203054
ISSN: 1177-5467
CID: 4951372

Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience

Fine, Robert L; Gulati, Anthony P; Krantz, Benjamin A; Moss, Rebecca A; Schreibman, Stephen; Tsushima, Dawn A; Mowatt, Kelley B; Dinnen, Richard D; Mao, Yuehua; Stevens, Peter D; Schrope, Beth; Allendorf, John; Lee, James A; Sherman, William H; Chabot, John A
PURPOSE/OBJECTIVE:We evaluated the efficacy and safety of capecitabine and temozolomide (CAPTEM) in patients with metastatic neuroendocrine tumors (NETs) to the liver. This regimen was based on our studies with carcinoid cell lines that showed synergistic cytotoxicity with sequence-specific dosing of 5-fluorouracil preceding temozolomide (TMZ). METHODS:A retrospective review was conducted of 18 patients with NETs metastatic to the liver who had failed 60 mg/month of Sandostatin LARâ„¢ (100%), chemotherapy (61%), and hepatic chemoembolization (50%). Patients received capecitabine at 600 mg/m(2) orally twice daily on days 1-14 (maximum 1,000 mg orally twice daily) and TMZ 150-200 mg/m(2) divided into two doses daily on days 10-14 of a 28-day cycle. Imaging was performed every 2 cycles, and serum tumor markers were measured every cycle. RESULTS:Using RECIST parameters, 1 patient (5.5%) with midgut carcinoid achieved a surgically proven complete pathological response (CR), 10 patients (55.5%) achieved a partial response (PR), and 4 patients (22.2%) had stable disease (SD). Total response rate was 61%, and clinical benefit (responders and SD) was 83.2%. Of four carcinoid cases treated with CAPTEM, there was 1 CR, 1 PR, 1 SD, and 1 progressive disease. Median progression-free survival was 14.0 months (11.3-18.0 months). Median overall survival from diagnosis of liver metastases was 83 months (28-140 months). The only grade 3 toxicity was thrombocytopenia (11%). There were no grade 4 toxicities, hospitalizations, opportunistic infections, febrile neutropenias, or deaths. CONCLUSIONS:CAPTEM is highly active, well tolerated and may prolong survival in patients with well-differentiated, metastatic NET who have progressed on previous therapies.
PMID: 23370660
ISSN: 1432-0843
CID: 3487292

The efficacy and safety of the capecitabine/temozolomide (CAPTEM) regimen in the treatment of well-differentiated neuroendocrine tumors with liver metastasis after failure of previous therapy: Columbia University Medical Center experience. [Meeting Abstract]

Oberstein, Paul Eliezer; Gulati, Anthony Paul; Krantz, Benjamin A.; Moss, Rebecca Anne; Schreibman, Stephen M.; Tsushima, Dawn; Mowatt, Kelley B.; Allendorf, John; Schrope, Beth; Lee, James A.; Sherman, William H.; Chabot, John A.; Fine, Robert
ISSN: 0732-183x
CID: 2995912

Treatment of multiple endocrine neoplasia 1/2 tumors: case report and review of the literature [Case Report]

Gulati, Anthony P; Krantz, Benjamin; Moss, Rebecca A; Moyal, Wendy N; Tsushima, Dawn A; Mowatt, Kelley B; Schreibman, Stephen; Fine, Robert L
BACKGROUND:Neuroendocrine tumors are uncommon tumors that are histopathologically and biologically heterogeneous and include the multiple endocrine neoplasia (MEN) 1 and 2 syndromes. The morbidity of MEN-1 and MEN-2 is often due to the symptomatology of the endocrine hormones produced, and the mortality mainly occurs from hepatic dysfunction incurred by liver metastases. At present, there is essentially no effective cure once the tumor has metastasized to the liver. PATIENT/METHODS:We present a patient with progressive, metastatic MEN-1 with the classic '3 P's' triad of neuroendocrine tumor of the pancreas, parathyroid adenoma and a pituitary adenoma. RESULTS:After progression on high-dose Sandostatin LAR (60 mg/month) and multiple surgeries, the patient had a partial response (40% decrease) to a novel regimen of capecitabine and temozolomide (CAPTEM) and progression-free survival of 18 months. He had minor grade 1 toxicities and no grade 2, 3 or 4 toxicities. DISCUSSION/CONCLUSIONS:The history and treatment options for MEN-1/2 cancers are reviewed, as well as the data behind our novel regimen, CAPTEM. CONCLUSION/CONCLUSIONS:The CAPTEM regimen is a tolerable, safe, easy to administer oral regimen with possible efficacy for MEN-1 tumors.
PMID: 23235517
ISSN: 1423-0232
CID: 4951362