Q+A: Gulam Manji, MD, PhD, on the Latest Advances in Pancreatic Cancer

Compared to other cancers, pancreatic cancer is relatively rare. Yet, it is the third leading cause of death from cancer in the United States, after lung and colorectal cancers. Pancreatic cancer makes up just 3% of all new cancer cases, but accounts for 8.3% of all cancer deaths. Only 12.5% of patients survive 5 years or more after diagnosis.  
 
Gulam Manji, MD, PhD, is a leading expert in pancreatic cancer and a physician-scientist devoted to conducting translational research with the overall goal of developing new treatments for cancer. As director of translational research for The Pancreas Center at Columbia University Irving Medical Center and member of the Herbert Irving Comprehensive Cancer Center (HICCC), Dr. Manji discusses recent advances in the field and new advances he's hoping to bring forward in pancreatic cancer care.

What makes pancreatic cancer so deadly?

Our patients can get a colonoscopy to screen for colon cancer or a mammogram to screen for breast cancer, but no such test exists for pancreas cancer. In most cases, symptoms are nonspecific, such as back pain and epigastric pain. Patients are symptomatically treated until the pain or discomfort doesn't go away and even worsens to the point where a CT scan is performed, and that's when the tumor is identified. Unfortunately, by the time the diagnosis is made, in nearly half of patients, the tumor has already spread.  
 
Those are some of the diagnostic issues that that we face. As far as treatment is concerned, the tumor is very fibrotic. Small islands of tumor cells are surrounded by a sea of stroma, which is this stiff material that doesn't allow treatments such as chemotherapies or targeted therapies to easily invade the tumor. So, the tumor grows in the pancreas surrounded by a sort of fort.

What have been some of the key treatment advances in recent years?

Since 2020, there have been a few exciting breakthroughs in the field. One of them is the availability of new drugs that target something called KRAS mutations, which are genetic changes found in tumors in over 90% of patients with pancreas cancer. KRAS is a switch that gets turned on inside the cell, and it's supposed to transmit a signal to tell the cell to divide and then turn off. However, this mutation leaves the switch persistently in an "on" state, where the cell continues to divide uncontrollably.  
 
For decades, researchers have tried to identify a drug that specifically targets this KRAS mutation and blocks it. The first one successfully targeted one type of mutation called KRAS G12C for patients with lung cancer, colon cancer, and pancreas cancers. Now, there are many different drugs that target more prevalent KRAS mutations, along with the KRAS protein itself, regardless of the mutation.

Describe the clinical trials that you are currently involved with.

The first clinical trial combines standard-of-care chemotherapy with immunotherapy and motixafortide, an experimental drug that is believed to help immunotherapy work better. Motixafortide interferes with a pathway that prevents T cells from entering the tumor. We showed in a very large study in mice that this combination not only controls the tumor for longer, but also allowed the mice to live longer. In a pilot study, we treated human patients and saw an overall decrease in the size of the tumor. Now the phase 2 clinical trial is active, where over 100 patients are being randomized to either get standard-of-care chemotherapy or this combination of chemotherapy, immunotherapy, and motixafortide.  
 
The second clinical trial is based on another immunosuppressive pathway involving adenosine triphosphate (ATP). Whenever there is tissue damage, ATP stored within the cell spills over to the outside of the cell, and certain enzymes metabolize the ATP to adenosine. There are specific receptors outside of the cell that measure the amount of adenosine. If there is a lot of adenosine, the immune cells are suppressed. We think that the tumor has hijacked this mechanism to dampen the immune response and favor tumor growth. The phase 1 clinical trial tests drugs that block this immune suppressive pathway in combination with chemotherapy.

What advice do you have for patients regarding clinical trials? 

Given the fact that the standard-of-care treatment options result in less than optimal treatment outcomes, every patient with pancreas cancer should enroll into a clinical trial. I truly feel that, with the help of patients participating in clinical trials, we are going to change in the near future how we treat pancreas cancer.