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Dr. Adam Snook
Thomas Jefferson University

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0 Cancer Immunotherapy
0 Immune System
0 Cancer Immunology
0 Cancer vaccine
0 Gastrointestinal cancer

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Cancer Immunotherapy
Immune System
Immune Responses
Cancer vaccine
Gastrointestinal cancer

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Journal article
Published: 01 June 2021 in Biomarkers in Medicine
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Parkinson’s disease (PD) is a highly prevalent and irreversible neurodegenerative disorder that is typically diagnosed in an advanced stage. Currently, there are no approved biomarkers that reliably identify PD patients before they have undergone extensive neuronal damage, eliminating the opportunity for future disease-modifying therapies to intervene in disease progression. This unmet need for diagnostic and therapeutic biomarkers has fueled PD research for decades, but these efforts have not yet yielded actionable results. Recently, studies exploring mechanisms underlying PD progression have offered insights into multisystemic contributions to pathology, challenging the classic perspective of PD as a disease isolated to the brain. This shift in understanding has opened the door to potential new biomarkers from multiple sites in the body. This review focuses on emerging candidates for PD biomarkers in the context of current diagnostic approaches and multiple organ systems that contribute to disease.

ACS Style

Lara Cheslow; Adam E Snook; Scott A Waldman. Emerging targets for the diagnosis of Parkinson’s disease: examination of systemic biomarkers. Biomarkers in Medicine 2021, 15, 597 -608.

AMA Style

Lara Cheslow, Adam E Snook, Scott A Waldman. Emerging targets for the diagnosis of Parkinson’s disease: examination of systemic biomarkers. Biomarkers in Medicine. 2021; 15 (8):597-608.

Chicago/Turabian Style

Lara Cheslow; Adam E Snook; Scott A Waldman. 2021. "Emerging targets for the diagnosis of Parkinson’s disease: examination of systemic biomarkers." Biomarkers in Medicine 15, no. 8: 597-608.

Review
Published: 24 May 2021 in Expert Opinion on Biological Therapy
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Introduction: Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and is the second leading cause of cancer-related death in the United States. Despite advances in early detection, ~25% of patients are late stage, and treated patients have <12% chance of survival after five years. Tumor relapse and metastasis are the main causes of patient death. Cancer stem cells (CSCs) are a rare population of cancer cells characterized by properties of self-renewal, chemo- and radio-resistance, tumorigenicity, and high plasticity. These qualities make CSCs particularly important for metastasis seeding, DNA-damage resistance, and tumor repopulating. Areas Covered: The following review article focuses on the role of CRC-SCs in tumor initiation, metastasis, drug resistance and tumor relapse, as well as on potential therapeutic options for targeting CSCs. Expert Opinion: Current studies are underway to better isolate and discriminate CR-CSCs from normal SCs, as well as from other types of CSCs, and to produce CSC-targeted therapeutics. The intestinal receptor, guanylate cyclase C (GUCY2C) could potentially provide a unique therapeutic target for both non-CSCs and CSCs alike in colorectal cancer (CRC) through immunotherapies. Indeed, immunotherapies targeting CSCs have the potential to break the treatment-recurrence cycle in the management of advanced malignancies.

ACS Style

Jessica Kopenhaver; Madison Crutcher; Scott A. Waldman; Adam E. Snook. The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission. Expert Opinion on Biological Therapy 2021, 1 -11.

AMA Style

Jessica Kopenhaver, Madison Crutcher, Scott A. Waldman, Adam E. Snook. The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission. Expert Opinion on Biological Therapy. 2021; ():1-11.

Chicago/Turabian Style

Jessica Kopenhaver; Madison Crutcher; Scott A. Waldman; Adam E. Snook. 2021. "The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission." Expert Opinion on Biological Therapy , no. : 1-11.

Review
Published: 04 May 2021 in Expert Opinion on Therapeutic Targets
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Gastrointestinal (GI) cancers account for the second leading cause of cancer-related deaths in the United States. Guanylyl cyclase C (GUCY2C) is an intestinal signaling system that regulates intestinal fluid and electrolyte secretion as well as intestinal homeostasis. In recent years, it has emerged as a promising target for chemoprevention and therapy for GI malignancies. The loss of GUCY2C signaling early in colorectal tumorigenesis suggests it could have a significant impact on tumor initiation. Recent studies highlight the importance of GUCY2C signaling in preventing colorectal tumorigenesis using agents such as linaclotide, plecanatide and sildenafil. Further, GUCY2C is a novel target for immunotherapy and a diagnostic marker of primary and metastatic disease. There is an unmet need for prevention and therapy in GI cancers. In that context, GUCY2C is a promising target for prevention, although the precise mechanisms by which GUCY2C signaling affects tumorigenesis remain to be defined. Further, clinical trials are exploring its role as an immunotherapeutic target for vaccines to prevent metastatic disease. Indeed, GUCY2C is an emerging target across the disease continuum from chemoprevention, to diagnostic management, through the treatment and prevention of metastatic disease.

ACS Style

Ariana A. Entezari; Adam E. Snook; Scott A. Waldman. Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential. Expert Opinion on Therapeutic Targets 2021, 25, 335 -346.

AMA Style

Ariana A. Entezari, Adam E. Snook, Scott A. Waldman. Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential. Expert Opinion on Therapeutic Targets. 2021; 25 (5):335-346.

Chicago/Turabian Style

Ariana A. Entezari; Adam E. Snook; Scott A. Waldman. 2021. "Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential." Expert Opinion on Therapeutic Targets 25, no. 5: 335-346.

Journal article
Published: 01 May 2021 in Immunotherapy
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Tweetable abstract US FDA-approved immune checkpoint inhibitors have limited efficacy for gastrointestinal cancers such as #colorectalcancer and #pancreaticcancer. Could combinations with experimental cancer ‘vaccines’ be the key?

ACS Style

Babar Bashir‡; John C Flickinger‡; Adam E Snook. Vaccines and immune checkpoint inhibitors: a promising combination strategy in gastrointestinal cancers. Immunotherapy 2021, 13, 561 -564.

AMA Style

Babar Bashir‡, John C Flickinger‡, Adam E Snook. Vaccines and immune checkpoint inhibitors: a promising combination strategy in gastrointestinal cancers. Immunotherapy. 2021; 13 (7):561-564.

Chicago/Turabian Style

Babar Bashir‡; John C Flickinger‡; Adam E Snook. 2021. "Vaccines and immune checkpoint inhibitors: a promising combination strategy in gastrointestinal cancers." Immunotherapy 13, no. 7: 561-564.

Journal article
Published: 01 March 2021 in Personalized Medicine
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Colorectal cancer continues to represent a significant burden on public health as the second highest cause of cancer mortality, when men and women are combined, in the US. About 50% of patients either present with late-stage metastatic disease, or develop metastatic recurrences, and ultimately die. In turn, this mortality largely reflects cancer stem cells, tumor-initiating cells that are responsible for cancer progression, drug resistance, recurrence and metastasis. This review summarizes the unique properties of colorectal cancer stem cells, and the emerging strategies by which they can be selectively targeted as a therapeutic approach to eradicating this disease.

ACS Style

Alicja Zalewski; Adam E Snook; Scott A Waldman. Stem cells as therapeutic targets in colorectal cancer. Personalized Medicine 2021, 18, 171 -183.

AMA Style

Alicja Zalewski, Adam E Snook, Scott A Waldman. Stem cells as therapeutic targets in colorectal cancer. Personalized Medicine. 2021; 18 (2):171-183.

Chicago/Turabian Style

Alicja Zalewski; Adam E Snook; Scott A Waldman. 2021. "Stem cells as therapeutic targets in colorectal cancer." Personalized Medicine 18, no. 2: 171-183.

Review
Published: 02 February 2021 in Expert Review of Precision Medicine and Drug Development
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Colorectal cancer (CRC) is one of the most-deadly malignancies worldwide. Current therapeutic regimens for CRC patients are relatively generic, based primarily on disease type and stage, with little variation. As the field of molecular oncology advances, so too must therapeutic management of CRC. Understanding molecular heterogeneity has led to a new-found promotion for precision therapy in CRC; underlining the diversity of molecularly targeted therapies based on individual tumor characteristics. We review current approaches for the treatment of CRC and discuss the potential of precision therapy in advanced CRC. We highlight the utility of the intestinal protein guanylyl cyclase C (GUCY2C), as a multi-purpose biomarker and unique therapeutic target. Here, we summarize current GUCY2C-targeted approaches for treatment of CRC. The GUCY2C biomarker has multi-faceted utility in medicine. Developmental investment of GUCY2C as a diagnostic and therapeutic biomarker offers a variety of options taking the molecular characteristics of cancer into account. From GUCY2C-targeted therapies, namely cancer vaccines, CAR-T cells, and monoclonal antibodies, to GUCY2C agonists for chemoprevention in those who are at high risk for developing colorectal cancer, the utility of this protein provides many avenues for exploration with significance in the field of precision medicine.

ACS Style

Amanda N. Lisby; John C. Flickinger Jr; Babar Bashir; Megan Weindorfer; Sanjna Shelukar; Madison Crutcher; Adam E. Snook; Scott A. Waldman. GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer. Expert Review of Precision Medicine and Drug Development 2021, 6, 117 -129.

AMA Style

Amanda N. Lisby, John C. Flickinger Jr, Babar Bashir, Megan Weindorfer, Sanjna Shelukar, Madison Crutcher, Adam E. Snook, Scott A. Waldman. GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer. Expert Review of Precision Medicine and Drug Development. 2021; 6 (2):117-129.

Chicago/Turabian Style

Amanda N. Lisby; John C. Flickinger Jr; Babar Bashir; Megan Weindorfer; Sanjna Shelukar; Madison Crutcher; Adam E. Snook; Scott A. Waldman. 2021. "GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer." Expert Review of Precision Medicine and Drug Development 6, no. 2: 117-129.

Journal article
Published: 01 February 2021 in Biomarkers in Medicine
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Gastrointestinal cancers encompass a diverse class of tumors arising in the GI tract, including esophagus, stomach, pancreas and colorectum. Collectively, gastrointestinal cancers compose a high fraction of all cancer deaths, highlighting an unmet need for novel and effective therapies. In this context, the transmembrane receptor guanylyl cyclase C (GUCY2C) has emerged as an attractive target for the prevention, detection and treatment of many gastrointestinal tumors. GUCY2C is an intestinally-restricted protein implicated in tumorigenesis that is universally expressed by primary and metastatic colorectal tumors as well as ectopically expressed by esophageal, gastric and pancreatic cancers. This review summarizes the current state of GUCY2C-targeted modalities in the management of gastrointestinal malignancies, with special focus on colorectal cancer, the most incident gastrointestinal malignancy.

ACS Style

John C Flickinger Jr; Jeffrey A Rappaport; Joshua R Barton; Trevor R Baybutt; Amanda M Pattison; Adam E Snook; Scott A Waldman. Guanylyl cyclase C as a biomarker for immunotherapies for the treatment of gastrointestinal malignancies. Biomarkers in Medicine 2021, 15, 201 -217.

AMA Style

John C Flickinger Jr, Jeffrey A Rappaport, Joshua R Barton, Trevor R Baybutt, Amanda M Pattison, Adam E Snook, Scott A Waldman. Guanylyl cyclase C as a biomarker for immunotherapies for the treatment of gastrointestinal malignancies. Biomarkers in Medicine. 2021; 15 (3):201-217.

Chicago/Turabian Style

John C Flickinger Jr; Jeffrey A Rappaport; Joshua R Barton; Trevor R Baybutt; Amanda M Pattison; Adam E Snook; Scott A Waldman. 2021. "Guanylyl cyclase C as a biomarker for immunotherapies for the treatment of gastrointestinal malignancies." Biomarkers in Medicine 15, no. 3: 201-217.

Review
Published: 29 January 2021 in Expert Opinion on Drug Discovery
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Introduction: Obesity is a prevalent condition that accounts for significant morbidity and mortality across the globe. Despite substantial effort, most obesity pharmacotherapies have proven unsafe or ineffective. The use of obese mouse models provides unique insight into the hormones and mechanisms that regulate appetite and metabolism. Paramount among these models are the ‘obese’ and ‘diabetic’ mice that revealed the powerful satiety hormone leptin, revolutionizing obesity research. Areas Covered: In this article, the authors discuss work on leptin therapy, and the clinical response to leptin in humans. The authors describe the use of modern mouse genetics to study targetable mechanisms for genetic forms of human obesity. Additionally, they describe mouse models of neuromodulation and their utility in unraveling neural circuits that govern appetite and metabolism. Expert opinion: Combining past and present models of obesity is required for the development of safe, effective, and impactful obesity therapy. Current research in obesity can benefit from repositories of genetically engineered mouse models to discover interactions between appetitive systems and circuits. Combining leptin therapy with other satiety signals comprising the gut-brain axis is a promising approach to induce significant enduring weight loss.

ACS Style

Joshua R. Barton; Adam E. Snook; Scott A. Waldman. From leptin to lasers: the past and present of mouse models of obesity. Expert Opinion on Drug Discovery 2021, 16, 777 -790.

AMA Style

Joshua R. Barton, Adam E. Snook, Scott A. Waldman. From leptin to lasers: the past and present of mouse models of obesity. Expert Opinion on Drug Discovery. 2021; 16 (7):777-790.

Chicago/Turabian Style

Joshua R. Barton; Adam E. Snook; Scott A. Waldman. 2021. "From leptin to lasers: the past and present of mouse models of obesity." Expert Opinion on Drug Discovery 16, no. 7: 777-790.

Journal article
Published: 01 December 2020 in Digestive Medicine Research
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ACS Style

Trevor R. Baybutt; Adam E. Snook. Bi-specific immunotherapy for gastrointestinal malignancies. Digestive Medicine Research 2020, 3, 83 -83.

AMA Style

Trevor R. Baybutt, Adam E. Snook. Bi-specific immunotherapy for gastrointestinal malignancies. Digestive Medicine Research. 2020; 3 ():83-83.

Chicago/Turabian Style

Trevor R. Baybutt; Adam E. Snook. 2020. "Bi-specific immunotherapy for gastrointestinal malignancies." Digestive Medicine Research 3, no. : 83-83.

Journal article
Published: 20 August 2020 in Journal for ImmunoTherapy of Cancer
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Background Adenovirus serotype 5 (Ad5) is a commonly used viral vector for transient delivery of transgenes, primarily for vaccination against pathogen and tumor antigens. However, endemic infections with Ad5 produce virus-specific neutralizing antibodies (NAbs) that limit transgene delivery and constrain target-directed immunity following exposure to Ad5-based vaccines. Indeed, clinical trials have revealed the limitations that virus-specific NAbs impose on the efficacy of Ad5-based vaccines. In that context, the emerging focus on immunological approaches targeting cancer self-antigens or neoepitopes underscores the unmet therapeutic need for more efficacious vaccine vectors. Methods Here, we evaluated the ability of a chimeric adenoviral vector (Ad5.F35) derived from the capsid of Ad5 and fiber of the rare adenovirus serotype 35 (Ad35) to induce immune responses to the tumor-associated antigen guanylyl cyclase C (GUCY2C). Results In the absence of pre-existing immunity to Ad5, GUCY2C-specific T-cell responses and antitumor efficacy induced by Ad5.F35 were comparable to Ad5 in a mouse model of metastatic colorectal cancer. Furthermore, like Ad5, Ad5.F35 vector expressing GUCY2C was safe and produced no toxicity in tissues with, or without, GUCY2C expression. Importantly, this chimeric vector resisted neutralization in Ad5-immunized mice and by sera collected from patients with colorectal cancer naturally exposed to Ad5. Conclusions These data suggest that Ad5.F35-based vaccines targeting GUCY2C, or other tumor or pathogen antigens, may produce clinically relevant immune responses in more (≥90%) patients compared with Ad5-based vaccines (~50%).

ACS Style

John C Flickinger Jr; Jagmohan Singh; Robert Carlson; Elinor Leong; Trevor R Baybutt; Joshua Barton; Ellen Caparosa; Amanda Pattison; Jeffrey A Rappaport; Jamin Roh; Tingting Zhan; Babar Bashir; Scott A Waldman; Adam E Snook. Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity. Journal for ImmunoTherapy of Cancer 2020, 8, e001046 .

AMA Style

John C Flickinger Jr, Jagmohan Singh, Robert Carlson, Elinor Leong, Trevor R Baybutt, Joshua Barton, Ellen Caparosa, Amanda Pattison, Jeffrey A Rappaport, Jamin Roh, Tingting Zhan, Babar Bashir, Scott A Waldman, Adam E Snook. Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity. Journal for ImmunoTherapy of Cancer. 2020; 8 (2):e001046.

Chicago/Turabian Style

John C Flickinger Jr; Jagmohan Singh; Robert Carlson; Elinor Leong; Trevor R Baybutt; Joshua Barton; Ellen Caparosa; Amanda Pattison; Jeffrey A Rappaport; Jamin Roh; Tingting Zhan; Babar Bashir; Scott A Waldman; Adam E Snook. 2020. "Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity." Journal for ImmunoTherapy of Cancer 8, no. 2: e001046.

Journal article
Published: 01 August 2020 in Future Medicinal Chemistry
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ACS Style

Adam E Snook. Companion vaccines for CAR T-cell therapy: applying basic immunology to enhance therapeutic efficacy. Future Medicinal Chemistry 2020, 12, 1 .

AMA Style

Adam E Snook. Companion vaccines for CAR T-cell therapy: applying basic immunology to enhance therapeutic efficacy. Future Medicinal Chemistry. 2020; 12 (15):1.

Chicago/Turabian Style

Adam E Snook. 2020. "Companion vaccines for CAR T-cell therapy: applying basic immunology to enhance therapeutic efficacy." Future Medicinal Chemistry 12, no. 15: 1.

Research paper
Published: 28 June 2020 in Cancer Biology & Therapy
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Most sporadic colorectal cancer reflects acquired mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, while germline heterozygosity for mutant APC produces the autosomal dominant disorder Familial Adenomatous Polyposis (FAP) with a predisposition to colorectal cancer. In these syndromes, loss of heterozygosity (LOH) silences the remaining normal allele of APC, through an unknown mechanism, as the initiating step in transformation. Guanylyl cyclase C receptor (GUCY2C) and its hormones, uroguanylin and guanylin, have emerged as a key signaling axis opposing mutations driving intestinal tumorigenesis. Indeed, uroguanylin and guanylin are among the most commonly repressed genes in colorectal cancer. Here, we explored the role of APC heterozygosity in mechanisms repressing hormone expression which could contribute to LOH. In genetic mouse models of APC loss, uroguanylin and guanylin expression were quantified following monoallelic or biallelic deletion of the Apc gene. Induced biallelic loss of APC repressed uroguanylin and guanylin expression. However, monoallelic APC loss in Apcmin/+ mice did not alter hormone expression. Similarly, in FAP patients, normal colonic mucosa (monoallelic APC loss) expressed guanylin while adenomas and an invasive carcinoma (biallelic APC loss) were devoid of hormone expression. Thus, uroguanylin and guanylin expression by normal intestinal epithelial cells persists in the context of APC heterozygosity and is lost only after tumor initiation by APC LOH. These observations reveal a role for loss of the hormones silencing the GUCY2C axis in tumor progression following biallelic APC loss, but not in mechanisms creating the genetic vulnerability in epithelial cells underlying APC LOH initiating tumorigenesis.

ACS Style

Amanda M. Pattison; Joshua R. Barton; Ariana A. Entezari; Alicja Zalewski; Jeff A. Rappaport; Adam E. Snook; Scott A. Waldman. Silencing the intestinal GUCY2C tumor suppressor axis requires APC loss of heterozygosity. Cancer Biology & Therapy 2020, 21, 799 -805.

AMA Style

Amanda M. Pattison, Joshua R. Barton, Ariana A. Entezari, Alicja Zalewski, Jeff A. Rappaport, Adam E. Snook, Scott A. Waldman. Silencing the intestinal GUCY2C tumor suppressor axis requires APC loss of heterozygosity. Cancer Biology & Therapy. 2020; 21 (9):799-805.

Chicago/Turabian Style

Amanda M. Pattison; Joshua R. Barton; Ariana A. Entezari; Alicja Zalewski; Jeff A. Rappaport; Adam E. Snook; Scott A. Waldman. 2020. "Silencing the intestinal GUCY2C tumor suppressor axis requires APC loss of heterozygosity." Cancer Biology & Therapy 21, no. 9: 799-805.

Editorial
Published: 23 June 2020 in Toxins
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The level of complexity in a disease like cancer presents a number of challenges for effective treatment development, which require significant innovation to overcome

ACS Style

Jessica Kopenhaver; Robert D. Carlson; Adam E. Snook. Mobilizing Toxins for Cancer Treatment: Historical Perspectives and Current Strategies. Toxins 2020, 12, 416 .

AMA Style

Jessica Kopenhaver, Robert D. Carlson, Adam E. Snook. Mobilizing Toxins for Cancer Treatment: Historical Perspectives and Current Strategies. Toxins. 2020; 12 (6):416.

Chicago/Turabian Style

Jessica Kopenhaver; Robert D. Carlson; Adam E. Snook. 2020. "Mobilizing Toxins for Cancer Treatment: Historical Perspectives and Current Strategies." Toxins 12, no. 6: 416.

Review
Published: 09 April 2020 in Toxins
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The ability of the immune system to precisely target and eliminate aberrant or infected cells has long been studied in the field of infectious diseases. Attempts to define and exploit these potent immunological processes in the fight against cancer has been a longstanding effort dating back over 100 years to when Dr. William Coley purposefully infected cancer patients with a cocktail of heat-killed bacteria to stimulate anti-cancer immune processes. Although the field of cancer immunotherapy has been dotted with skepticism at times, the success of immune checkpoint inhibitors and recent FDA approvals of autologous cell therapies have pivoted immunotherapy to center stage as one of the most promising strategies to treat cancer. This review aims to summarize historic milestones throughout the field of cancer immunotherapy as well as highlight current and promising immunotherapies in development.

ACS Style

Robert D. Carlson; Jr. John C. Flickinger; Adam E. Snook; John Jr. Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy. Toxins 2020, 12, 241 .

AMA Style

Robert D. Carlson, Jr. John C. Flickinger, Adam E. Snook, John Jr. Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy. Toxins. 2020; 12 (4):241.

Chicago/Turabian Style

Robert D. Carlson; Jr. John C. Flickinger; Adam E. Snook; John Jr. 2020. "Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy." Toxins 12, no. 4: 241.

Research paper
Published: 09 February 2020 in Cancer Biology & Therapy
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Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis

ACS Style

Erik S. Blomain; Jeffrey A. Rappaport; Amanda M. Pattison; Babar Bashir; Ellen Caparosa; Jonathan Stem; Adam E. Snook; Scott A. Waldman. APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis. Cancer Biology & Therapy 2020, 21, 441 -451.

AMA Style

Erik S. Blomain, Jeffrey A. Rappaport, Amanda M. Pattison, Babar Bashir, Ellen Caparosa, Jonathan Stem, Adam E. Snook, Scott A. Waldman. APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis. Cancer Biology & Therapy. 2020; 21 (5):441-451.

Chicago/Turabian Style

Erik S. Blomain; Jeffrey A. Rappaport; Amanda M. Pattison; Babar Bashir; Ellen Caparosa; Jonathan Stem; Adam E. Snook; Scott A. Waldman. 2020. "APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis." Cancer Biology & Therapy 21, no. 5: 441-451.

Journal article
Published: 01 October 2019 in American Journal of Physiology-Cell Physiology
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Enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood death from diarrhea and the leading cause of Traveler’s diarrhea. E. coli heat-stable enterotoxin (ST) is a major virulence factor of ETEC and inhibits the brush border Na/H exchanger NHE3 in producing diarrhea. NHE3 regulation involves multiprotein signaling complexes that form on its COOH terminus. In this study, the hypothesis was tested that ST signals via members of the Na/H exchanger regulatory factor (NHERF) family of scaffolding proteins, NHERF2, which had been previously shown to have a role, and now with concentration on a role for NHERF3. Two models were used: mouse small intestine and Caco-2/BBe cells. In both models, ST rapidly increased intracellular cGMP, inhibited NHE3 activity, and caused a quantitatively similar decrease in apical expression of NHE3. The transport effects were NHERF3 and NHERF2 dependent. Also, mutation of the COOH-terminal amino acids of NHERF3 supported that NHERF3-NHERF2 heterodimerization was likely to account for this dual dependence. The ST increase in cGMP in both models was partially dependent on NHERF3. The intracellular signaling pathways by which ST-cGMP inhibits NHE3 were different in mouse jejunum (activation of cGMP kinase II, cGKII) and Caco-2 cells, which do not express cGKII (elevation of intracellular Ca2+concentration [Ca2+]i). The ST elevation of [Ca2+]iwas from intracellular stores and was dependent on NHERF3-NHERF2. This study shows that intracellular signaling in the same diarrheal model in multiple cell types may be different; this has implications for therapeutic strategies, which often assume that models have similar signaling mechanisms.

ACS Style

Tiane Chen; Ruxian Lin; Leela Rani Avula; Rafiquel Sarker; Jianbo Yang; Boyoung Cha; Chung Ming Tse; George McNamara; Ursula Seidler; Scott Waldman; Adam Snook; Marcel J.C. Bijvelds; Hugo R De Jonge; Xuhang Li; Mark Donowitz. NHERF3 is necessary forEscherichia coliheat-stable enterotoxin-induced inhibition of NHE3: differences in signaling in mouse small intestine and Caco-2 cells. American Journal of Physiology-Cell Physiology 2019, 317, C737 -C748.

AMA Style

Tiane Chen, Ruxian Lin, Leela Rani Avula, Rafiquel Sarker, Jianbo Yang, Boyoung Cha, Chung Ming Tse, George McNamara, Ursula Seidler, Scott Waldman, Adam Snook, Marcel J.C. Bijvelds, Hugo R De Jonge, Xuhang Li, Mark Donowitz. NHERF3 is necessary forEscherichia coliheat-stable enterotoxin-induced inhibition of NHE3: differences in signaling in mouse small intestine and Caco-2 cells. American Journal of Physiology-Cell Physiology. 2019; 317 (4):C737-C748.

Chicago/Turabian Style

Tiane Chen; Ruxian Lin; Leela Rani Avula; Rafiquel Sarker; Jianbo Yang; Boyoung Cha; Chung Ming Tse; George McNamara; Ursula Seidler; Scott Waldman; Adam Snook; Marcel J.C. Bijvelds; Hugo R De Jonge; Xuhang Li; Mark Donowitz. 2019. "NHERF3 is necessary forEscherichia coliheat-stable enterotoxin-induced inhibition of NHE3: differences in signaling in mouse small intestine and Caco-2 cells." American Journal of Physiology-Cell Physiology 317, no. 4: C737-C748.

Preprint content
Published: 30 September 2019
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A growing class of immunotherapeutic agents work by redirecting components of the immune system to recognize specific markers on the surface of cancer cells and initiate a selective immune response. However, such immunotherapeutic modalities will remain confined to a relatively small subgroup of patients until two major hurdles are overcome: (1) the specific targeting of cancer cells relative to healthy cells, and (2) the lack of common targetable tumor biomarkers among all patients. Here, we designed a unique class of agents that exploit the inherent acidic microenvironment of solid tumors to selectively graft the surface of cancer cells with immuno-engager epitopes for directed destruction by components of the immune system. Specifically, conjugates were assembled using an antigen that recruit antibodies present in human serum, and the pH(Low) Insertion Peptide (pHLIP), a unique peptide that selectively target tumorsin vivoby anchoring onto cancer cell surfaces in a pH-dependent manner. We established that conjugates can recruit antibodies from human serum to the surface of cancer cells, and induce complement-dependent and antibody-dependent cellular cytotoxicity by peripheral blood mononuclear cells and also an engineered NK cell line. These results suggest that these agents have the potential to be applicable to treating a wide range of solid tumors and to circumvent the problem of narrow windows of selectivity.

ACS Style

Janessa Wehr; Eden L. Sikorski; Elizabeth Bloch; Mary S. Feigman; Noel J. Ferraro; Trevor Baybutt; Adam E. Snook; Marcos M. Pires; Damien Thévenin. pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity. 2019, 785402 .

AMA Style

Janessa Wehr, Eden L. Sikorski, Elizabeth Bloch, Mary S. Feigman, Noel J. Ferraro, Trevor Baybutt, Adam E. Snook, Marcos M. Pires, Damien Thévenin. pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity. . 2019; ():785402.

Chicago/Turabian Style

Janessa Wehr; Eden L. Sikorski; Elizabeth Bloch; Mary S. Feigman; Noel J. Ferraro; Trevor Baybutt; Adam E. Snook; Marcos M. Pires; Damien Thévenin. 2019. "pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity." , no. : 785402.

Review
Published: 01 May 2019 in Regenerative Medicine
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Gastrointestinal cancers remain a tremendous burden on society. Despite advances in therapy options, including chemotherapy and radiation, cancer mortality from recurrences and metastases occur frequently. Cancer stem cells (CSCs) drive disease recurrence and metastasis, as these cells are uniquely equipped to self-renew and evade therapy. Therefore, cancer eradication requires treatment strategies that target CSCs in addition to differentiated cancer cells. This review highlights current literature on therapies targeting CSCs in gastrointestinal cancer.

ACS Style

Jonathan Stem; John C Flickinger Jr; Dante Merlino; Ellen M Caparosa; Adam Snook; Scott A Waldman. Therapeutic targeting of gastrointestinal cancer stem cells. Regenerative Medicine 2019, 14, 331 -343.

AMA Style

Jonathan Stem, John C Flickinger Jr, Dante Merlino, Ellen M Caparosa, Adam Snook, Scott A Waldman. Therapeutic targeting of gastrointestinal cancer stem cells. Regenerative Medicine. 2019; 14 (4):331-343.

Chicago/Turabian Style

Jonathan Stem; John C Flickinger Jr; Dante Merlino; Ellen M Caparosa; Adam Snook; Scott A Waldman. 2019. "Therapeutic targeting of gastrointestinal cancer stem cells." Regenerative Medicine 14, no. 4: 331-343.

Journal article
Published: 23 April 2019 in Journal for ImmunoTherapy of Cancer
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Background The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. Methods Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. Results All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. Conclusions Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. Trial registration This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737

ACS Style

Adam E. Snook; Trevor R. Baybutt; Bo Xiang; Tara S. Abraham; John C. Flickinger; Terry Hyslop; Tingting Zhan; Walter K. Kraft; Takami Sato; Scott A. Waldman. Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. Journal for ImmunoTherapy of Cancer 2019, 7, 104 .

AMA Style

Adam E. Snook, Trevor R. Baybutt, Bo Xiang, Tara S. Abraham, John C. Flickinger, Terry Hyslop, Tingting Zhan, Walter K. Kraft, Takami Sato, Scott A. Waldman. Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. Journal for ImmunoTherapy of Cancer. 2019; 7 (1):104.

Chicago/Turabian Style

Adam E. Snook; Trevor R. Baybutt; Bo Xiang; Tara S. Abraham; John C. Flickinger; Terry Hyslop; Tingting Zhan; Walter K. Kraft; Takami Sato; Scott A. Waldman. 2019. "Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients." Journal for ImmunoTherapy of Cancer 7, no. 1: 104.

Journal article
Published: 02 February 2019 in Human Pathology
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Colorectal cancers (CRCs) initiate through distinct mutations, including in APC pathway components leading to tubular adenomas (TAs); in BRAF, with epigenetic silencing of CDX2, leading to serrated adenomas (SAs); and in the DNA mismatch repair machinery driving microsatellite instability (MSI). Transformation through the APC pathway involves loss of the hormone GUCA2A that silences the tumor suppressing receptor GUCY2C. Indeed, oral hormone replacement is an emerging strategy to reactivate GUCY2C and prevent CRC initiation and progression. Moreover, retained expression by tumors arising from TAs has established GUCY2C as a diagnostic and therapeutic target to prevent and treat metastatic CRC. Here, we defined the potential role of the GUCA2A-GUCY2C axis, and its suitability as a target, in tumors arising through the SA and MSI pathways. GUCA2A hormone expression was eliminated in TAs, SAs and MSI tumors compared to their corresponding NATs. In contrast to the hormone, the tumor suppressing receptor GUCY2C was retained in TA and MSI tumors. Surprisingly, GUCY2C expression was nearly eliminated in SAs reflecting loss of the transcription factor CDX2. Changes in the GUCA2A-GUCY2C axis in human SAs and MSI tumors were precisely recapitulated in genetic mouse models. These data reveal the possibility of GUCA2A loss silencing GUCY2C in the pathophysiology of, and oral hormone replacement to restore GUCY2C signaling to prevent, MSI tumors. Also, they highlight the potential for targeting GUCY2C to prevent and treat metastases arising from TA and MSI tumors. In contrast, loss of GUCY2C excludes patients with SAs as candidates for GUCY2C-based prevention and therapy.

ACS Style

Babar Bashir; Dante J. Merlino; Jeffrey A. Rappaport; Esteban Gnass; Juan P. Palazzo; Ying Feng; Eric R. Fearon; Adam E. Snook; Scott A. Waldman. Silencing the GUCA2A-GUCY2C tumor suppressor axis in CIN, serrated, and MSI colorectal neoplasia. Human Pathology 2019, 87, 103 -114.

AMA Style

Babar Bashir, Dante J. Merlino, Jeffrey A. Rappaport, Esteban Gnass, Juan P. Palazzo, Ying Feng, Eric R. Fearon, Adam E. Snook, Scott A. Waldman. Silencing the GUCA2A-GUCY2C tumor suppressor axis in CIN, serrated, and MSI colorectal neoplasia. Human Pathology. 2019; 87 ():103-114.

Chicago/Turabian Style

Babar Bashir; Dante J. Merlino; Jeffrey A. Rappaport; Esteban Gnass; Juan P. Palazzo; Ying Feng; Eric R. Fearon; Adam E. Snook; Scott A. Waldman. 2019. "Silencing the GUCA2A-GUCY2C tumor suppressor axis in CIN, serrated, and MSI colorectal neoplasia." Human Pathology 87, no. : 103-114.