Enhancing the Effectiveness of Chemotherapy for Pancreatic Cancer: A Phase II Clinical Trial
Researchers at Winship Cancer Institute at Emory University in Atlanta, Georgia are currently investigating whether and how two older drugs, paricalcitol and hydroxychloroquine, impact pancreatic cancer when used alongside established chemotherapy. The phase II clinical trial investigates how well paricalcitol and hydroxychloroquine work when combined with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer.
According to Vidula Sukhatme, founder of Global Cures, the impetus for this trial came from the experience of Dr. Stephen Bigelsen, an allergy and asthma physician diagnosed with metastatic pancreatic cancer. Bigelsen researched potential therapies for his disease and developed his own protocol. His research, experience and success-to-date laid the foundation for the work currently being done at Emory.
“This clinical trial is notable because a physician who was also a patient did the initial research and chose this experimental regimen for himself. Emory designed their trial based on his experience and results. Finally, and most importantly, Dr. Bigelsen continues to do well,” Sukhatme explained.
Bigelsen, whose Ca 19-9 levels at diagnosis were 11,575U/ml — a normal range being 0-37U/ml — was treated with mitomycin, gemcitabine and capecitabine plus intravenous paricalcitol (25mcg) three times a week as well as hydroxychloroquine (600mg) twice daily. While his results only represent a single case, he now has no evidence of active disease on his scans and his Ca 19-9 levels are 16U/ml more than four years later.
“In this instance, you have Bigelsen’s outcome data and then you look at the mechanisms behind what he did. And you ask, could that work?” Sukhatme said.
In solid tumor cancers, both normal tissues and malignant cells are supported by host tissue stroma. This stroma, over the course of the disease progression, will alter and eventually begin to promote tumor growth, invasion and metastasis. This will lead to the development of carcinoma-associated fibroblasts (CAFs) which, in turn, play a role in further tumor progression. These CAFs also play a role in a tumor’s resistance to drug therapy.
Based on Bigelsen’s experience, the Emory researchers hypothesize that paricalcitol, a form of Vitamin D, can temporarily cease the harmful activity of these CAFs and break through the stroma that is protecting the tumor. The hope is that this will help maximize the penetration of the chemotherapeutic drugs and thus reduce tumor growth and spread.
Hydroxychloroquine, on the other hand, is a part of the trial because of its role as an autophagy inhibitor. Autophagy is a process that allows cells to consume and recycle altered, unused organelles and cellular components. This enables cancer cells, which rapidly divide and require a great deal of energy, to conserve their energy and rid themselves of toxins. For a deep dive into autophagy and cancer, see this journal article.
Autophagy plays an important role in pancreatic cancer tumor progression. According to the Pancreatic Cancer Action Network, more than ninety percent of pancreatic cancers feature what is known as a KRAS genetic mutation. One impact of a KRAS mutation is the upregulation of autophagy. Accordingly, most pancreatic cancer cells show increased autophagic activity, even appearing to depend on the process for their survival.
When chemotherapeutic agents attack pancreatic cancer cells, these cells need to conserve even more energy than normal, making autophagy that much more crucial to their survival. By combining chemotherapy with an agent that inhibits autophagy such as hydroxychloroquine, the cancer cells will hopefully be unable to meet their own energetic demands, thus enhancing the activity of the chemotherapy on the cells and preventing their growth and progression.
To see if you or a loved one might qualify for the clinical trial at Emory University’s Winship Cancer Institute, visit this webpage, call 404-778-1900 or email Principal Investigator Bassel F. El-Rayes at [email protected].
“If a patient is not near Atlanta and can’t be a part of this trial,” Sukhatme urges, “consider taking this information in to your treating physician for their review. Dr. Bigelsen’s results provide some hope for patients of pancreatic cancer.”
To dive deeper into Dr. Bigelsen’s story, you can see an interview his sister did with him in December 2020. A relevant quote from the accompanying post: “If you are diagnosed with a terminal illness where conventional treatment has no real evidence of extending life beyond a short period of time-consider a clinical trial or combining experimental treatment with conventional treatment immediately. Do not wait until conventional treatment fails, because by then it may be too late to save your life.”
As always, this article is not a substitute for medical advice. Always consult your healthcare provider for medical guidance.