Genetically enhanced drug-drug combination could improve care of patients with cachexia syndrome

Clinicians at GW Cancer Center have engineered biologically enhanced tumor-specific targeting agents that provided patients with significantly enhanced cancer treatment benefits. The development of a genetically enhanced long-acting drug therapy for cachexia syndrome has been reported in this weeks edition of ACS Sustainable Chemistry and Engineering. It was chosen as anSselect article for June.

Cachexia is a severe form of chronic wasting disease that causes loss of control over body functions and renders patients vulnerable to many forms of cancer. In many cases patients may go into a vegetative state leading to physical deterioration and eventual death. Cachexia is often managed with ongoing chemotherapy and sometimes medical marijuana but it can also occur in conjunction with surgery andor radiation. There are no curative interventions. Targeted therapy options include chemotherapy radiation or oral pharmacologic treatment however while the best available therapies provide adequate pain relief limited efficacy andor severe adverse effects. A recent literature review by Dragomir Matos senior study author and director of the Molecular Biophysics Department at the GW Institute for Translational Medicine and Science (ITMS) examined the use of engineered drug-drug conjugates (EDCs) to treat cachexia. A team led by Matos conducted a systematic review of EDCs against known CTC-induced killing signals (TCKs) in pancreatic cancer; a CTC-selective tumor (Cancer cells from chronic pancreatitis patients) subtype; in murine pancreatic cancer and rat liver cancer; and in triple-negative breast cancer and KRAS-mutant renal cell carcinoma. The review compared the efficacy and safety profiles of EDCs against TCKs in controlled experimental and laboratory conditions.

In experimental studies EDCs selectively targeted and eliminated TCKs in pancreatic cancer mice with the most potent combination (60-mgkg) but not in the control group. In the rat liver and murine liver carcinoma xenografts EDCs that were administered at the lowest dose (100-mgkg) and increased to 1000-mgkg (dose escalation to 900-mgkg) significantly increased tumor growth compared to EDCs administered at the highest dose seen in control groups. EDCs performing well in mouse experiments did not increase T levels at three months in either cancer subtype. However EDCs had greater synergistic anti-tumor activity than EDCs administered at the highest dose seen in control groups. Tregs (regulatory elements localized at the cell surface) did not affect tumor growth in either tumor subtype. These data Matos said indicate that the engineered EDCs have superior pharmacological efficacy compared to EDCs administered at the lowest dose in cachexia-induced cellular toxicity the most common type of treatment resistance in cancer cells with high frequency cachexia.

Topical application of EDC to cachexia patients.

Our datas findings suggest that drug formulation and multi-dose studies are needed to explore the safety and efficacy of modified agents for tumor-specific treatment resistance he said. Hopefully our work will provide direction and substantiate clinical studies and guide treatment research addressing cachexia-specific andor high T cell response.