Faculty Interests Database

Faculty Affairs: Faculty Interests Database Scott A. Waldman, MD, PhD

Pharmacology & Experimental Therapeutics
Thomas Jefferson University
Jefferson Medical College
Department of Biochemistry & Molecular Pharmacology

Thomas Jefferson University
Jefferson Medical College
Department of Medicine
Division of Clinical Pharmacology

Mailing Address Contact Information
1020 Locust Street, 368JAH
Philadelphia, Pennsylvania 19107
United States
Phone: (215) 955-6086
Fax: (215) 955-5681
Expertise and Research Interests
1. GUCY2C is a molecular target in GI malignancies

Colorectal cancer is the fourth leading cause of cancer and the second leading cause
of cancer-related death in the US and the world. There is a paucity of tumor-
specific molecular targets against which imaging and therapeutic agents can be
directed in this disease. We discovered that GUCY2C is selectively expressed
normally on apical membranes of intestinal epithelial cells from the duodenum to the
distal rectum, but not in other normal tissues. Also, we demonstrated that GUCY2C is
universally over-expressed on primary and metastatic colorectal cancer cells, but
not on other tumor cells arising outside the gastrointestinal tract. These data
suggest that GUCY2C is a highly specific molecular target to direct novel
therapeutic and imaging agents against metastatic colorectal tumors. Indeed, GUCY2C-
targeted imaging agents detect millimeter colorectal cancer metastases in liver.
Moreover, GUCY2C-targeted cytotoxins kill metastatic colorectal tumors in mouse
models in vivo. Beyond colorectal cancer, we discovered that GUCY2C is ectopically
expressed in extra-intestinal GI malignancies including esophageal, gastric and
pancreatic cancers and can serve as a novel target for those tumors as well. GUCY2C-
targeted imaging and therapeutic platforms have been licensed to Millennium
Pharmaceuticals which has advanced these technologies into registration trials in
gastric, esophageal and pancreatic cancer (ClinicalTrials.gov Identifiers:
NCT02202759, NCT02391038, NCT02202785, NCT02056015).

2. GUCY2C is a biomarker for managing patients with GI malignancies

Beyond targeted imaging and therapy, selective expression in colorectal tumors
suggests that GUCY2C could serve as a novel molecular marker for detecting
metastatic cancer cells in tissues outside the intestine.1 Indeed, GUCY2C is a
highly sensitive and specific biomarker of metastatic colorectal cancer cells in
human tissues. We developed and validated an analytical platform to quantify GUCY2C
mRNA expression in human tissues using the reverse transcriptasepolymerase chain
reaction (RT-qPCR). We applied this assay to detect occult metastatic tumor cells in
regional lymph nodes in stage I-II colorectal cancer patients in a prospective
multicenter blinded clinical trial. These analyses revealed that the presence of
occult tumor cells in regional lymph nodes detected by GUCY2C RT-qPCR was the most
powerful marker of prognosis in stage I-II colorectal cancer patients. Moreover, we
advanced this platform to quantify occult tumor burden across the entire regional
lymph node network, which precisely identified stage I-II patients as high risk,
with nearly 100% likelihood of developing recurrent metastatic disease, or low risk,
with virtually no risk of developing recurrence. This platform has been licensed to
DiagnoCure and is marketed as Previstage". We continue to advance this technology to
predict which stage I-II colorectal cancer patients will respond to adjuvant
chemotherapy, and for the management of patients with extra-intestinal GI

Other Expertise
3. Paracrine Hormone Hypothesis of Colorectal Cancer

GUCY2C is the receptor for the paracrine hormone guanylin in the colorectum.
Guanylin is the most commonly lost gene product in colorectal cancer, it is lost
universally across all patients at the earliest stages of transformation, and its
loss is a tumorigenic mechanism which is conserved across species. These
characteristics suggest the intriguing hypothesis that colorectal cancer is a
disease that initiates, at least in part, by loss of the paracrine hormone guanylin
which silences the tumor suppressing receptor GUCY2C contributing to transformation.
Indeed, the guanylin-GUCY2C axis is an essential regulator of homeostatic processes
along the dynamic crypt-surface epithelial axis in intestine including proliferation
and the cell cycle; energetic programming and the Warburg metabolic phenotype; DNA
damage sensing and repair; survival signaling; and epithelial-mesenchymal
interactions contributing to desmoplasia. Moreover, silencing the GUCY2C signaling
axis promotes intestinal tumor initiation and progression.

4. GUCY2C is a novel immunological target for the secondary prevention of metastatic
disease in GI malignancies

While immunotherapy has emerged as a transformative approach for some cancers, there
is a shortage of antigenic targets for vaccines that are tumor-specific, highly
effective, provide life-long protection, and spare normal tissues. Our studies
identified a novel class of vaccine targets, the cancer mucosa antigens, which are
normally expressed in the mucosal, but not the systemic, compartment and continue to
be universally expressed by metastatic tumors cells arising from those mucosae.
These antigenic targets leverage limited cross-talk between mucosae and systemic
immune systems, preventing mucosal destruction by systemic immune responses, and
limited immunological tolerance in the systemic compartment to mucosal antigens,
facilitating therapeutic responses against metastatic disease. Indeed, GUCY2C, the
index example of a cancer mucosa antigen, has been incorporated into an adenoviral
delivery system, which produces highly specific and efficacious anti-GUCY2C
responses, including CD8 T cell, antibody and memory T cell responses that provide
durable life-long protection in mice in prophylactic and therapeutic models of
metastatic colorectal cancer. Therapeutic protection is achieved without inducing
adverse events, including inflammatory bowel disease. This novel immunological
approach has been translated to patients with stage I-II colorectal cancer, and we
have inoculated the first 10 patients with our adenoviral GUCY2C vaccine
(ClinicalTrials.gov Identifier: NCT01972737). To date, this vaccine has been safe
and well-tolerated, producing CD8 T cell and antibody responses in patients. We are
advancing these paradigms, integrating DNA and viral vaccines into prime-boost
strategies and developing adoptive T cell approaches incorporating chimeric antigen
receptors (CARs) targeting GUCY2C, to treat and prevent metastases in patients with
colorectal and extra-intestinal GI malignancies.
Industrial Relevance
5. A novel GUCY2C gut-brain endocrine axis at the intersection of obesity and metabolic

While guanylin is the paracrine hormone regulating GUCY2C in the colorectum,
uroguanylin regulates this receptor in the small intestine. Unexpectedly, GUCY2C
knockout mice developed diet-induced obesity and the metabolic syndrome. We discovered
that this reflects a novel gut-brain endocrine axis in which feeding induces the
secretion of prouroguanylin from the intestine into blood, which circulates to the
brain where it is processed into active hormone and regulates GUCY2C expressed by
leptin-responsive neurons in the hypothalamus and dopaminergic neurons in the
substantia nigra to regulate satiety, appetite, and feeding.
Signal transduction; guanylyl cyclases; cyclic GMP; intestinal epithelial cell biology; crypt-villus homeostasis; proliferation and the cell cycle; metabolic programming; DNA damage and repair; epithelial-mesenchymal interactions; GI malignancies; colorectal cancer; esophageal cancer; gastric cancer; molecular diagnostics; targeted imaging agents; targeted therapeutics; cancer mucosal antigens; cancer vaccines
  • Last 3 Years Of Publications
  • 280. Waldman, S.A. and Terzic, A. (2015) Clinical Pharmacology and Therapeutics: The Next Five Years. Clin. Pharmacol. Ther. 97:2-6.
  • 281. Waldman, S.A. and Terzic, A. (2015) Companion diagnostics at the intersection of personalized medicine and health care delivery. Biomarkers Med. 9:1-3.
  • 282. Rodriguez, E., Hobson, G.M., Armani, M.H., Sakowski, L., Kreiger, P.A., Zhu, Y., Waldman, S.A., and Shaffer, T.H. (2015) Duplication of the PLP1gene inhibits airway responsiveness and induces lung inflammation in a mouse model of PelizaeusMerzbacher disease. Pulm. Pharm. Ther. 30:22-31.
  • 283. Krishnan, V., Xu, X., Kelly, D., Yang, X., Snook, A.E., Waldman, S.A., Mason, R.W., Jia, X., and Rajasekaran, A.K. (2015) CD-19-targeted nanodelivery of doxorubicin enhances therapeutic efficacy in B-cell acute lymphoblastic leukemia. Mol. Pharmaceutics 12:2101-2111.
  • 284. Waldman, S.A., and Terzic, A. (2015) Bioinnovation enterprise: An engine driving breakthrough therapies. Clin. Pharmacol. Ther. 99:8-13.
  • 285. Lin, J.E., Colon-Gonzalez, F., Blomain, E., Kim, G.W., Aing, A., Stoecker, B., Rock, J., Snook, A.E., Zhan, T., Hyslop, M. Tomczak, M., Blumberg, R.S., and Waldman, S.A. (2016) Calories suppress guanylin silencing the GUCY2C tumor suppressor in colorectal cancer in obesity. Cancer Res. 76:339-346. (Editors Choice: Science Translational Medicine 8:325:325ec22; recommended in F1000Prime as being of special significance in its field).
  • 286. Waldman, S.A., and Terzic, A. (2016) Big data transforms discovery-utilization therapeutics continuum. Clin. Pharmacol. Ther. 99:250-254.
  • 287. Blomain, E. and Waldman, S.A. (2016) Does obesity promote the development of colorectal cancer? Expert Rev. Anticancer Ther. 24:1-3.
  • 288. Blomain, E., Pattison, A., and Waldman, S.A. (2016) GUCY2C ligand replacement to prevent colorectal cancer. Cancer Biol. Ther. 17:713-718.
  • 289. Kim, G.W., Lin, J.E., Snook, A.E., Aing, A., Merlino, D.J., Li, P., and Waldman, S.A. (2016) Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity. Nutr. Diabetes (Nature Publishing Group) 23;6:e211. doi: 10.1038/nutd.2016.18. PMID:27214655.
  • 290. Blomain, E., Merlino, D.J., Pattison, A., Snook, A.E., and Waldman, S.A. (2016) GUCY2C hormone axis at the intersection of obesity and colorectal cancer. Mol. Pharm. 90:199-204.
  • 291. Cantarin, M.P.M., Keith, S., Doria, C., Frank, A., Maley, W., Ramirez, C., Lallas, C., Sha, A., Waldman, S.A., and Falkner, B. (2016) Association of inflammation prior to kidney transplantation with post-transplant diabetes mellitus. CardioRenal Med. 6:289-300.
  • 292. Pattison, A.M., Blomain, E.S., Merlino, D.J., and Waldman, S.A. (2016) The GUCY2C signaling axis and colon cancer prevention. World J Gastroenterology 22:8070-8077.
  • 293. Myers, R.E., Wolf, T., Shwae, P, Hegarty, S., Peiper, S.C., and Waldman, S.A. (2016) Physician receptivity to molecular diagnostic testing and readiness to act on results for early stage colon cancer patients. BMC Cancer 16:766-775.
  • 294. Pattison, A.M., Blomain, E.S., Wang, F., Crissey, M.A.S., Kraft, C.L., Merlino, D.J., Snook, A.E., Lynch, J.P., and Waldman, S.A. (2016) Intestinal enteroids model GUCY2C-dependent secretion induced by heat-stable enterotoxins. Infect. Immun. 84:3083-3091.
  • 295. Waldman, S.A. and Atta-Ur-Rahman (2016) Ferid Murad at 80: A legacy of Science, Medicine, and Mentorship. Curr. Med. Chem. 23:2556-2558.
  • 296. Waldman, S.A. and Terzic, A. (2016) Managing innovation to maximize value along the discovery-translation-application continuum. Clin. Pharm. Therap. 10:8-12.
  • 297. Pattison, A.M., Abraham, T.S., Merlino, D.J., Lin, J.E., Saw, T.A., Snook, A.E., and Waldman, S.A. (2016) Targeting guanylate cyclase C in colorectal cancer: where are we now? Drugs Future 22:8070-8077.
  • 298. Magee, M.S., Marszalowicz, G.P., Li, P., Waldman, S.A. and Snook, A.E. (2016) GUCY2C-directed CAR-T cells oppose colorectal cancer metastases without autoimmunity. Oncoimmunology 5:e1227897.
  • 299. Snook, A.E., Baybutt, T.R., Hyslop, T., and Waldman, S.A. (2016) Preclinical evaluation of a replication-deficient recombinant adenovirus serotype 5 vaccine expressing guanylate cyclase C and the PADRE epitope. Human Gene Ther Methods. 27:238-250.
  • 300. Jozef Bartunek, Andre Terzic, Beth Davison, Gerasimos Filippatos, Slavica Radovanovic, Branko Beleslin, Bela Merkely, Piotr Musialek, Wojciech Wojakowski, Peter Andreka, Ivan Horvath, Amos Katz, Dariouch Dolatabadi, Badih El Nakadi, Aleksandra Arandjelovic, Istvan Edes, Petar Seferovic, Slobodan Obradovic, Marc Vanderheyden, Nikola Jagic, Ivo Petrov, Shaul Atar, Majdi Halabi, Valeri Gelev, Michael Shochat, Jaroslaw Kasprzak, Ricardo Sanz Ruiz, Guy R. Heyndrickx, Noémi Nyolczas, Victor Legrand, Antoine Guédès, Alex Heyse, Tiziano Mocetti, Fernando Fernandez-Aviles, Pilar Jimenez-Quevedo, Antoni Bayes Genis, Flavio Ribichini, Marcin Gruchala, Scott A. Waldman, John R. Teerlinck, Bernard J. Gersh, Thomas J. Povsic, Timothy D. Henry, Marco Metra, Roger Hajjar, Michael Tendera, Atta Behfar, Bertrand Alexandre, Aymeric Seron, Wendy Gattis Stough, Warren Sherman, Gad Cotter, William Wijns, for the CHART program. (2016) Cardiopoietic cell therapy for advanced ischemic heart failure: Results at 39-weeks of the prospective, randomized, double-blind, sham-controlled CHART-1 clinical trial. Eur. Heart J. 38:648-660.
  • 301. Waldman, S.A. and Terzic, A. (2017) Clinical Pharmacology & Therapeutics: Past, Present, and Future. Clin. Pharm. Ther. 101:300-303.
  • 302. Aka, A., Rappaport, J., Pattisson, A., Snook, A., and Waldman, SA. (2017) Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer. Expert Rev. Clin. Pharmacol. 10:549-557.
  • 303. Weinberg, D.S., Lin, J.E., Foster, N.R., DellaZanna, G., Umar, A., Seisler, D., Kraft, W.K., Kastenberg, D.M., Katz, L.C., Limburg, P.J., and Waldman, S.A. (2017) Bioactivity of oral linaclotide in human colorectum for cancer chemoprevention. Cancer Prev. Res. 10:345-354. (Selected as cover image and article).
  • 304. Xiang, B., Berman-Booty, L., Magee, M.S., Waldman, S.A., Alexeev, V.Y. and Snook, A.E. (2017) Synergistic DNA + adenovirus prime-boost immunization produces high avidity effector CD8+ T cells to eliminate metastatic colorectal cancer. J Immuno. 198:3507-3514.
  • 305. Chervoneva, I., Freydin, B., Hyslop, T., and Waldman, S.A. (2017) Modeling qRT-PCR dynamics with application to cancer biomarker quantification. Stat. Meth. Med. Res. Jan 1:962280216683204. doi: 10.1177/0962280216683204.
  • 306. Wei, Q., Zhong Ye, Z., Zhong, X., Li, L., Wang, C., Myers, R.E., Palazzo, J.P., Yan, A., Waldman, S.A., Chen, X., Jiang, B., Xing, J., Li, B., and Yang, H. (2017) Multiregion high-depth whole exome sequencing of matched primary and metastatic tumors revealed inter- and intra-individual genomic heterogeneity and polyclonal seeding in colorectal cancer metastasis. Annals Oncology 28:2135-2141.
  • 307. Waldman, S.A. and Terzic, A. (2017) Peer review certifies quality and innovation in Clinical Pharmacology & Therapeutics. Clin. Pharm. Ther. 102:373-377.
  • 308. Li, P., Wuthrick, E., Rappaport, J.A., Kraft, C., Lin, J.E., Marszalowicz, G., Snook, A.E., Hyslop, T.M., Zhan, T., and Waldman, S.A. (2017) GUCY2C prevents the acute radiation-induced GI syndrome by p53 rescue of mitotic catastrophe. Cancer Res. 77:5095-5106. (Selected as cover image and article).
  • 309. Li, P., Lin, J.E., Snook, A.E., and Waldman, S.A. (2017) ST-producing enterotoxigenic E. coli oppose carcinogen-induced colorectal tumorigenesis in mice. Toxins 9: 279, doi:10.3390.
  • 310. Waldman, S.A. and Terzic, A. (2017) Process improvement for maximized therapeutic innovation outcomes. Clin. Pharm. Ther. In press.
  • 311. Kraft, C.L., Rappaport, J.A., Snook, A.E., Lin, E.J., Kim, G.W., Lynch, J.P., and Waldman, S.A. (2017) GUCY2C maintains the intestinal stem cell niche by opposing ER stress. Oncotarget (In press).
  • 312. Sherman, A., Bartunek, J., Dolatabadi, D., Sanz-Ruiz, R., Beleslin, B., Wojakowski, W., Heyndrickx, G., Kimpalou, J.K., Waldman, S.A., Laarman, G.-J., Seron, A., Behfar, A., Latere, J.-P., Terzic, A., Wijns, W. for the Chart Program. First-in-human use of a novel catheter for endomyocardial cell delivery. JACC: Cardiovascular Interventions (In press).
  • 313. Magee, M.S., Marszalowicz, G.P., Prajapati, P., Hersperger, A.R., Waldman, S.A. and Snook, A.E. (2017) Human GUCY2C-targeted chimeric antigen receptor (CAR)-expressing T cells eliminate colorectal cancer metastases. Cancer Immunology Research (In press).

Last Updated by Scott Waldman, MD, PhD: Wednesday, October 14, 2009 1:59:37 PM

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