Pancreatic cancer remains one of the most challenging cancers to treat, with historically low survival rates. However, recent breakthroughs are offering new avenues for therapeutic intervention, focusing on previously overlooked protein interactions and innovative immunotherapy approaches. Scientists are increasingly focused on understanding the mechanisms that drive the aggressiveness of the disease, and several promising targets have emerged in the last year.
Targeting SPP1 to Halt Cancer Spread
Researchers at The Institute of Cancer Research, London, announced in the discovery of a key protein, SPP1, that could be targeted with drugs to treat pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of the disease. PDAC accounts for 90 percent of pancreatic cancer cases. The findings, published in Nature, demonstrate that blocking SPP1 could potentially stop the spread of cancer and improve survival times.
The study analyzed data from 644 patients’ tumors and found a correlation between higher levels of SPP1 and worse patient outcomes. Laboratory tests using pancreatic cancer organoids – lab-grown mini-tumors – showed that switching off the gene responsible for producing SPP1 resulted in fewer and smaller tumors, and a reduction in the most dangerous, invasive cells. In mice with PDAC, disabling the gene significantly extended survival; while none of the mice with the active gene survived past 50 days, 20 percent of those without the gene lived to 400 days.
Pancreatic cancer has stubbornly resisted improvements in survival rates over the past 50 years, with only five in 100 people surviving for ten years or more. More than 10,000 people are diagnosed with pancreatic cancer each year in the UK, with over 9,000 fatalities annually.
USP25: Disrupting Oxygen Supply to Cancer Cells
Another promising area of research centers on the protein USP25, described as a ‘recycler’ protein. Research led by Professor Axel Behrens at the Institute of Cancer Research in London suggests that USP25 plays a crucial role in allowing cancer cells to adapt to low-oxygen environments. Cancer cells require a substantial energy supply to grow rapidly, and often outstrip their oxygen supply. The protein HIF-1a enables the formation of new blood vessels to increase oxygen delivery. USP25 appears to ‘recycle’ HIF-1a, allowing cancer cells to continue growing even with limited oxygen.
Initial laboratory tests indicated that deleting the USP25 gene or blocking its action reduced cancer cell growth by starving them of oxygen. This suggests that USP25 could be a valuable target for drug development, not only for pancreatic cancer but also for other tumors reliant on a large oxygen supply, such as breast cancer. This work was published in Nature Communications earlier in . Researchers are now focused on designing molecules to block USP25’s action, with the hope of initiating clinical trials within the next five years.
A ‘One-Product-Fits-All’ Immunotherapy Approach
UCLA researchers have developed a novel immunotherapy, CAR-NKT cell therapy, that demonstrates potential for treating pancreatic cancer, even after it has metastasized. Published in PNAS on , the study details how the therapy can locate and destroy pancreatic tumors.
This therapy utilizes engineered immune cells that can be mass-produced from donated blood stem cells and stored for immediate use. This “off-the-shelf” approach offers a significant advantage over current personalized cell therapies, which can be extremely expensive (hundreds of thousands of dollars) and require weeks of manufacturing time – a critical factor for patients with rapidly progressing pancreatic cancer. The estimated cost of a dose of CAR-NKT cell therapy is approximately $5,000.
Zenocutuzumab Offers Hope for Younger Patients
A new drug, zenocutuzumab (Bizengri), is also showing promise, particularly for younger patients with pancreatic cancer. Zenocutuzumab targets NRG1 fusion, which is present in approximately 1% of pancreatic cancers. The drug was identified as a potential treatment for Colin Kiesel, a patient diagnosed with pancreatic cancer.
Challenges and Future Directions
Despite these advances, pancreatic cancer remains a formidable challenge. Over 70% of patients do not receive any treatment at all. The difficulty in early diagnosis, coupled with the aggressive nature of the disease, contributes to the poor prognosis. The research into SPP1, USP25, CAR-NKT cell therapy, and zenocutuzumab represents significant steps forward, but further research and clinical trials are essential to translate these discoveries into effective treatments for a wider range of patients. The focus on targeting specific proteins and leveraging the power of the immune system offers a renewed sense of hope in the fight against this devastating disease.
