CPP is working collaboratively with research institutions and nonprofit groups to support clinical trials in Gastric Cancer, Pediatric Cancers, and early-onset Type 1 Diabetes
Gastric adenocarcinoma is a leading global cause of cancer mortality, and the leading global infection-associated cancer. H. pylori is the most common bacterial infection in humans, and causes gastritis in all individuals. Gastritis progresses along the “Correa cascade” from gastritis to the precancerous stages of chronic atrophic gastritis (CAG) and intestinal metaplasia (IM), to gastric adenocarcinoma. The validated Correa histopathology score provides quantitative assessment of the gastric mucosa, including changes over time and with interventions.
This project will directly evaluate, for the first time, the role of polyamines in human gastric inflammation and carcinogenesis. Altered L- arginine/polyamine metabolism has been implicated in immune dysregulation and DNA damage caused by H. pylori. Polyamines have been implicated in carcinogenesis due to effects on epithelial cell growth and apoptosis, and levels are increased in H. pylori gastritis
This Phase 2 trial will investigate the efficacy of CPP-1X in subjects ages 30-69 with gastric premalignant lesions in high-risk regions of Latin America. The primary endpoint is gastric epithelial cell DNA damage, measured at the 6-month time point, assessed by percent positive cells in each patient. Gastric precancerous lesions are defined as chronic atrophic gastritis (CAG) and intestinal metaplasia (IM). Patients will be clinically assessed with endoscopy and gastric biopsy at four time points: 0, 6, 18, and 24 months. Overall, the efficacy of CPP-1X will be assessed by its effect on: 1) DNA damage, 2) histology scoring, and 3) gastric polyamine levels.
Neuroblastoma (NB) is the most common extracranial pediatric cancer and accounts for 8-10% of pediatric malignancies and 12-15% of pediatric cancer deaths in children. The clinical presentation is highly variable, ranging from a mass that causes no symptoms to a primary tumor that causes critical illness as a result of local invasion, widely disseminated disease, or both. There are four main categories of neuroblastoma, very low risk, low risk, intermediate risk, and high risk. The 5-year survival rate for all types of neuroblastoma is 74%. Long-term survival occurs primarily in patients with very low risk, low risk or intermediate risk disease. Long-term survival is dependent on achieving complete tumor remission.
Current standard therapy for high-risk neuroblastoma treatment has four phases: induction of remission, local control with surgery and radiotherapy, consolidation with high-dose chemotherapy and autologous stem cell rescue, and maintenance with immunotherapy/differentiation therapy. Neuroblastoma cells uniformly express GD2 on their cell surfaces. Chimeric-anti-GD2 antibody, called ch14.18, has been developed for use as part of an immunotherapy cassette in alternating cycles with differentiation therapy. Combined anti‐GD2 antibody (ch14.18) Unituxin, IL‐2, GM‐CSF and isotretinoin is now the standard US FDA‐approved therapy in North America for patients with neuroblastoma after autologous hematopoietic stem cell transplantation. Despite improvements with intensified therapy as described in the preceding paragraph, high-risk neuroblastoma (NB) still portends a poor prognosis, with approximately 50% of patients failing to respond to therapy or relapsing, leaving an unmet critical need to improve upon current therapies with more tumor targeted regimens.
The most common genetic alteration in NB is MYCN where amplifications occur in approximately 20-25% of all cases and are associated with the high-risk phenotype. ODC1 encodes for ornithine decarboxylase the first enzyme in polyamine synthesis in mammals and is a direct transcriptional target of MYC. ODC1 and other genes in the polyamine pathway are crucial elements of MYCN oncogenesis in neuroblastoma. High ODC1, either in the presence or absence of MYCN amplifications, correlates with poor clinical outcome of reduced event free survival (EFS) and overall survival (OS).
Based on preclinical and early phase studies, CPP’s lead product CPP-1X holds promise to treat/prevent tumors associated with neuroblastoma. CPP is participating with expert investigators at Children’s Oncology Group (COG) to explore trials in children with neuroblastoma. Currently CPP is supporting a COG-led and NCI funded Phase 2 trial evaluating CPP-1X in combination with Unituxin and chemotherapy in subjects with relapsed refractory NB.
Early-onset Type 1 Diabetes
Type 1 diabetes (T1D) is an organ-specific autoimmune disease that accounts for 5-10% of diabetes in the United States (US). It commonly occurs in childhood and adolescence but T1D can be initially diagnosed at any age. T1D is characterized by progressive immune-mediated destruction of pancreatic β-cells leading to partial, or in most cases, absolute insulin deficiency. Recent-onset, also referred to as new-onset, T1D is currently characterized by the date of clinical diagnosis. At the time of diagnosis, 15-30% of a person’s β-cells may still be functional and producing insulin. Shortly after diagnosis as β-cell toxicity from hyperglycemia improves exogenous insulin requirements generally decrease, as endogenous insulin production increases. Patients become clinically symptomatic when approximately 90% of pancreatic β-cells are destroyed. Therefore, preserving β-cell function is a target for promising treatments.
One novel pathway with the potential to impact β-cell health involves polyamines, which are small molecules that are important in governing cell growth, proliferation, and survival. The activity of ODC is upregulated in early diabetic kidney disease, contributing to renal hypertrophy and hyperfiltration. Preclinical studies have demonstrated that CPP-1X can preserve β-cell function and delay diabetes onset in animals.
Based on preclinical studies, CPP’s lead product, CPP-1X, holds promise to treat/prevent early onset Type 1 Diabetes. CPP is participating with expert investigators at the University of Indiana in a Phase I clinical trial evaluating CPP-1X in Early Onset T1D to preserve β-cell function and delay diabetes onset.