Breakthrough Clinical Results
Oncotelic Therapeutics announced the publication of a study in the *International Journal of Molecular Sciences* showing that TGFB2 gene methylation is a positive prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC), particularly in patients with low CD8+ T-cell infiltration. The study, conducted in collaboration with Sapu Biosciences, found that patients with high TGFB2 methylation and low expression of immune markers had a significantly longer median overall survival (over 50 months). This finding supports further clinical development of Oncotelic's investigational antisense oligonucleotide, OT-101, in PDAC, especially in patients with these characteristics. The study also highlights the importance of profiling TGFB methylation to better characterize tumor immune status and select candidates for immunotherapy.
Key Highlights
- TGFB2 gene methylation identified as a positive prognostic biomarker for pancreatic cancer.
- Patients with high TGFB2 methylation and low CD8+ T-cell infiltration showed significantly improved overall survival (over 50 months).
- Findings support further clinical development of OT-101, Oncotelic's investigational antisense oligonucleotide, in pancreatic cancer.
- Study underscores the importance of profiling TGFB methylation for patient selection in immunotherapy.
Incidence and Prevalence
Global Epidemiology of Pancreatic Cancer
Incidence and Prevalence
Pancreatic cancer is currently the seventh leading cause of cancer-related deaths worldwide with 432,242 related deaths in 2018. More recent data indicates that in 2015, pancreatic cancer resulted in 411,600 deaths globally. The worldwide incidence of pancreatic cancer is about 185,000 cases per year.
Unlike other cancers, the incidence of pancreatic cancer continues to increase, with little improvement in survival rates. Worldwide, the mortality-incidence ratio approaches 98%, indicating that almost 100% of pancreatic cancer cases are fatal.
Geographic Distribution
The highest incidence rates are found in North America and Western Europe, with lower rates in Asian Africa. Age-standardized incidence rates are 7.2 and 2.8 per 100,000 populations for high and low incidence regions respectively. The incidence in the developed world parallels that in the United States, while incidence in undeveloped nations is lower but may be underreported.
Demographic Patterns
Pancreatic cancer has been increasing overall, but patterns differ by demographic group and histologic type. In the United States, incidence rates declined between the 1970s and 1990s but increased from 1994 to 2013 among White males. Among non-Hispanic White and Hispanic males, the annual percent change (APC) in incidence between 1992 and 2013 was 0.84% and 0.73%, respectively.
Rates also rose among White non-Hispanic, Hispanic and Asian females (APC = 0.81%, 0.56% and 1.23%, respectively). Rates increased even more rapidly among females aged 25-34 years (APC > 2.5%). Rates among Black males and females remained unchanged, but higher compared with other racial/ethnic groups.
In Georgia (USA), African Americans displayed a significantly higher age-adjusted incidence (14.6/100,000) and mortality rate (13.3/100,000), compared to Caucasians, showing racial disparities in disease burden. There is an increase in incidence predicted, particularly in African Americans.
Survival Rates
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 7%. In the United States, pancreatic cancer is currently the third deadliest cancer with a 5-year survival rate of only 12%.
Despite advances in treatment over the past two decades, 5-year overall survival rates for resected pancreatic cancer with modern therapies remain around 20-25%. Using the criteria of observed 5-year survival, less than 2% of all pancreatic cancer patients are alive.
After R0-resection (complete surgical removal), the median survival time is between 17 and 28 months, after R1/2-resection between 8 and 22 months. First-line therapy achieves a median overall survival of less than 12 months.
Risk Factors
Epidemiological studies prove smoking and chronic alcohol consumption as causes of about 30% of pancreatic cancers. The most significant risk factor appears to be cigarette smoking, with a risk ratio of about 2. Alcohol and coffee consumption have been reported as possible risks in some (but not in most) studies. Diet is probably a significant factor, but is difficult to evaluate quantitatively.
Future Projections
Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Having a better understanding of worldwide and regional epidemiologic features and risk factors of pancreatic cancer is essential to identify new approaches for prevention, early diagnosis, surveillance, and treatment.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Pancreatic Cancer Treatment
Immune Checkpoint Inhibitors (ICIs)
Recent research has identified several promising approaches for pancreatic cancer treatment through immune checkpoint modulation:
- CD40 agonists have emerged as important immunotherapeutic agents that enhance both innate and adaptive immunity
- CD40 activation enables dendritic cells to prime tumor-specific T cells, shifts macrophages to a pro-inflammatory state, activates B cells, and helps remodel tumor fibrosis
- While showing modest antitumor activity alone, some patients experience durable responses when CD40 agonists are combined with other therapies like immune checkpoint inhibitors and chemotherapy
- A risk score system based on three immune checkpoints (OX40, TNFSF14 and KIR3DL1) has been established as an independent prognostic factor
- OX40 has been identified as an independent prognosis-related gene, with higher expression linked to increased survival rates
- The B7 family immune checkpoints (PD-L1, PD-L2, B7-H3, B7-H4, VISTA, HHLA2) are involved in tumor progression through immune-dependent and non-immune-dependent pathways
- A novel anti-PD-L1/CXCR4 bispecific nanobody has shown promise by binding to two targets on cancer cells and inhibiting CXCL12-induced cell migration
Tumor Microenvironment (TME) Targeting
The tumor microenvironment plays a crucial role in pancreatic cancer development:
- TME targeting strategies focused on vasculature, immune checkpoints, and immuno-cell therapies have led to revolutionary clinical interventions
- Novel therapeutic approaches aim to disrupt cell-cell and cell-mediators interactions between TME components and tumor cells
- Irreversible electroporation (IRE) ablation therapy has been shown to promote immune infiltration and conversion of CD4T cells into anti-tumor IFN-γTh1 cells and Th17 cells
- PD-L1 blockade enhances activation of CD11b+CD103- type-2 conventional dendritic cells (cDC2s) and their antigen presentation to CD4T cells after ablation
- IL-6 and PD-L1 dual blockade significantly increases the ratio of IFN-γTh1 in CD4T cells to boost anti-tumor immunity of NK cells
PARP Inhibitors and DNA Damage Response
- Olaparib, a PARP inhibitor, has demonstrated anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2
- ATF3 (activating transcription factor 3) enhances olaparib resistance through the NF-κB signaling pathway
- Maintenance therapy approaches are being explored following the success of the POLO trial with olaparib
- Combination of DNA demethylating agent 5-AZA with HDAC inhibitor SAHA has shown effectiveness in promoting degradation of mutant p53, upregulating p21, and downregulating c-Myc and BRCA-1
Novel Combination Approaches
- The combination therapy of ICIs has proven safe and effective for treating advanced pancreatic cancer, especially when combined with chemotherapy and radiotherapy
- Patients with a high TMB (tumor mutational burden) showed longer median overall survival compared to those with low TMB (19.3 vs 7.2 months)
- NIZ985 (recombinant heterodimer of IL-15 and IL-15 receptor α) in combination with spartalizumab (anti-PD-1 antibody) has shown antitumor activity
- BRD4 inhibitors enhanced the efficacy of oncolytic adenoviruses in 3D co-culture models of PDAC and in vivo xenografts
- RNAseq analysis showed BRD4 inhibitors increased viral E1A expression, altered expression of cell cycle regulators and inflammatory factors, and attenuated expression of tumor cell oncogenes like c-Myc and Myb
Despite these advances, ICIs have not yet achieved a breakthrough in pancreatic cancer therapy, with FDA-approval existing only for the small subgroup of MSI-H/dMMR tumors.
Drug used in other indications
Trabedersen (OT-101) Indications and Clinical Applications
Based on the provided information, trabedersen (also known as AP-12009) is a synthetic antisense oligodeoxynucleotide specifically designed to block the production of TGFbeta2, a secreted protein that can exert protumor effects.
Therapeutic Indications
Beyond pancreatic cancer, trabedersen is indicated for the treatment of:
- Malignant brain tumors
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Solid tumors overexpressing TGFbeta2, such as those of the:
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Skin
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Colon
Clinical Evidence and Trial Results
The development of trabedersen has progressed through several stages of clinical evaluation:
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Preclinical studies demonstrated that trabedersen:
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Reduced the secretion of TGFbeta2 in cultured tumor cells
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Exhibited antitumor activity ex vivo
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Showed safety in animal models with chronic intracerebral or intravascular administration without life-threatening side effects
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Early clinical trials in patients with advanced cancer confirmed the safety observations seen in animal studies
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A phase IIb trial showed:
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Improved survival in patients with brain tumors who received intratumoral administration of trabedersen
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This improvement was in comparison to patients receiving standard chemotherapy
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Currently, validation of these observations is being sought through an ongoing large-scale, phase III, randomized, controlled trial
The clinical development of trabedersen represents a targeted approach to cancer therapy by specifically inhibiting a protein known to promote tumor growth and progression.