Pancreatic Cancers Treated Better By Breaking Up Scar Tissue

Despite advances in cancer treatment, tumors of the pancreas remain among the most difficult to treat. To date, pancreatic cancers remain largely resistant to immune-based therapies, despite the successes of immunotherapies in treating lung cancers and melanomas.

A new study from Washington University School of Medicine in St. Louis that was published in the journal Nature Medicine, has shown that immunotherapy against pancreatic cancer can shrink these tumors if they are given in combination with drugs that break up the fibrous scar tissue in these tumors.

Physicians at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital are using the strength of these data to conduct a phase 1 clinical trial in patients with advanced pancreatic cancer. This clinical trial will test the safety of this drug combination when given alongside standard chemotherapy.

“Pancreatic tumors are notoriously unresponsive to both conventional chemotherapy and newer forms of immunotherapeutics,” said senior author David G. DeNardo, PhD, an assistant professor of medicine. “We suspect that the fibrous environment of the tumor that is typical of pancreatic cancer may be responsible for the poor response to immune therapies that have been effective in other types of cancer.”

Pancreatic cancers are unusual among cancers since they characteristically consist of large swaths of scar tissue. These balls of fibrous tissue that surround the tumor create a protective environment for cancer cells. These scar tissue-based capsules prevent the immune system accessing the tumor cells and also limit the exposure of these tumors to chemotherapies that have been administered through the bloodstream. DeNardo and his colleagues used a mouse model of pancreatic cancer to determine if disrupting these fibrous capsules could sensitize pancreatic tumors to chemotherapy regimens.

Pancreatic tumors are surrounded by a protective "nest" made of fibrotic scar tissue and the cells that manufacture it (red). A new study demonstrates that disrupting this fibrous tissue makes immune therapy and chemotherapy more effective in attacking tumors of the pancreas. (Image: DeNardo Lab)
Pancreatic tumors are surrounded by a protective “nest” made of fibrotic scar tissue and the cells that manufacture it (red). A new study demonstrates that disrupting this fibrous tissue makes immune therapy and chemotherapy more effective in attacking tumors of the pancreas. (Image: DeNardo Lab)

“Proteins called focal adhesion kinases are known to be involved in the formation of fibrous tissue in many diseases, not just cancer,” DeNardo said. “So we hypothesized that blocking this pathway might diminish fibrosis and immunosuppression in pancreatic cancer.”

Focal adhesion kinase (FAK) is a protein (encoded by the PTKs gene) that controls cell adhesion and cell motility. Inhibiting FAK activity in breast cancer cells makes them less likely to spread to other organs (see Chan, K.T., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200809110). Small molecules have been designed that can readily inhibit FAK, and DeNardo and his colleagues used FAK inhibitors against pancreatic cancer in combination with immunotherapy.

Focal Adhesion Kinase

In their mouse study, an investigational FAK inhibitor was administered to mice in combination with a clinically approved immune therapy that activates the patient’s own T-cells so that they can effectively attack tumor cells.

Mice that had pancreatic cancer survived no longer than two months when given either a FAK inhibitor or immune therapy alone. If the FAK inhibitors were added to standard chemotherapy, the tumor response improved over chemotherapy alone. However, the three-drug combination that consisted of FAK inhibitors, immune therapy and chemotherapy, displayed the best outcomes in laboratory studies and more than tripled survival times in some mice. Some were still alive without evidence of progressing disease at six months after treatment and beyond.

The success of this mouse study provided a strong rationale for testing this drug combination in patients with advanced pancreatic cancer, according to oncologist Andrea Wang-Gillam, MD, PhD, an associate professor of medicine, who was involved with this research.

“This trial is one of about a dozen we are conducting specifically for pancreatic cancer at Washington University,” she said. “We hope to improve outcomes for these patients, especially since survival with metastatic pancreatic cancer is typically only six months to a year. The advantage of our three-pronged approach is that we are attacking the cancer in multiple ways, breaking up the fibers of the tumor microenvironment so that more immune cells and more of the chemotherapy drug can attack the tumor.”

Pancreatic Cancer Stem Cells Could Be “Suffocated” by an Anti-Diabetic Drug

A new study by researchers from Queen Mary University of London’s Barts Cancer Institute and the Spanish National Cancer Research Centre (CNIO) in Madrid shows that pancreatic cancer stem cells (PancSCs) are very dependent on oxygen-based metabolism, and can be “suffocated” with a drug that is already in use to treat diabetes.

Cancer cells typically rely on glycolysis; a metabolic pathway that degrades glucose without using oxygen. However, it turns out that not all cancer cells are alike when it comes to their metabolism.

PancSCs use another metabolic process called oxidative phosphorylation or OXPHOS to completely oxidize glucose all the way to carbon dioxide and water. OXPHOS uses large quantities of oxygen and occurs in the mitochondria. However, this is precisely the process that is inhibited by the anti-diabetic drug, metformin.

Ever crafty, some PancSCs manage to adapt to such a treatment by varying their metabolism, and this leads to a recurrence of the cancer. However, this English/Spanish team thinks that they have discovered a way to prevent such resistance and compel all PancSCs to keep using OXPHOS. This new discovery might open the door to new treatments that stop cancer stem cells using oxygen and prevent cancers from returning after conventional treatments. A clinical trial is planned for later next year.

Dr Patricia Sancho, first author of the research paper, said: “We might be able to exploit this reliance on oxygen by targeting the stem cells with drugs that are already available, killing the cancer by cutting off its energy supply. In the long-term, this could mean that pancreatic cancer patients have more treatment options available to them, including a reduced risk of recurrence following surgery and other treatments.”

PancSCs become resistant to metformin by suppressing a protein called MYC and increasing the activity of a protein called PGC-1α. However, this resistance mechanism of PancSCs can be abolished if a drug called menadione is given. Menadione increases the amount of reactive oxygen species in mitochondria. Additionally, resistance to metformin can be prevented or even reversed if the MYC protein is inhibited by genetic or pharmacological means. Therefore, the specific metabolic features of pancreatic Cancer Stem Cells are amendable to therapeutic intervention and can provide the basis for developing more effective therapies to combat this lethal cancer.

Pancreatic cancer is still one of the most difficult cancer types to treat. It rarely causes symptoms early on and does not usually trigger diagnosis until its later and more advanced stages. Unfortunately, many patients do not live longer than a year after being diagnosed. These cancers are also becoming more common due to obesity, which increases the patient’s risk for metabolic syndrome and diabetes, which are pancreatic cancer risk factors. Limited treatment options and a failure to improve survival rates mean that finding new treatment strategies is a priority.

PancSCs could be an important but as yet overlooked piece of this puzzle, since they compose only a small proportion of the tumor. PancSCs also have the potential to make new tumors, even if all the other cells are killed, and are prone to spreading around the body (metastasis). Therefore killing these PancSCs is a better way to treat such dangerous cancers.