Novel Drug offers Promise for Patients with Ovarian or Pancreatic Cancers

Surgery. Removal of cancerous ovarian tumors
Surgery. Removal of cancerous ovarian tumors.

Ovarian and pancreatic cancer are known as two of the most lethal cancers.  In addition, they are often called ‘silent killers’ since they rarely have early symptoms. As a result, ovarian and pancreatic cancer frequently go undetected until they are diagnosed in advantaged stages and treatment options are limited.

According to the Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, each year, about 20,000 women in the United States are diagnosed with ovarian cancer.  And while the cancer accounts for only about 3% of all cancers in women, it causes more deaths than any other cancer of the female reproductive system.

Pancreatic cancer, the ninth most common cancer in women and the tenth most common cancer in men, accounts for approximate 7% of all cancer deaths. According to the American Cancer Society, this year, an estimated 56,770 adults (29,940 men and 26,830 women) in the United States will be diagnosed with this diseases. In addition, it is estimated that 45,750 deaths (23,800 men and 21,950 women) from this disease will occur this year.

Potential treatment
Cancer scientists at Houston Methodist and The University of Texas MD Anderson Cancer Center have been vigilant about looking for more effective late-stage treatments and may have found one.

Stephen T. Wong, Ph.D is John S. Dunn, Sr. Presidential Distinguished Chair in Biomedical Engineering, Research Institute, Professor of Computer Science and Bioengineering in Oncology, Institute for Academic Medicine and Associate Director, Cores, Biostatistics and Bioinformatics at Houston Methodist and Weill Cornell Medical College

Because ovarian cancer is often diagnosed discovered when the disease is in an advanced stage, treatment usually begins with surgery to remove as much of the cancer as possible. To eliminate remaining cancer cells, chemotherapy, which often includes a combination a platinum-based drug such as carboplatin (Paraplatin) or cisplatin with a taxane such as paclitaxel (Taxol®; Bristol-Myers Squibb Company) or docetaxel (Taxotere®; Sanofi-Genzyme), is considered an essential second step in treatment. In some cases, treatment involved neoadjuvant chemotherapy, which means that chemotherapy is given ahead surgery to helps shrink the tumor, making it easier to remove.

For early stage pancreatic cancer, surgery is performed if a patient is a candidate. This is generally followed by adjuvant chemotherapy therapy or chemotherapy in combination with radiation. If, however, surgery is not an option, neoadjuvant chemotherapy and/or radiation are given, generally with the goal of shrinking the tumor so that surgery can be performed later.

The standard of care for metastatic pancreatic cancer is typically one of two chemotherapy regimens: FOLFIRINOX (5-FU, leucovorin, irinotecan and oxaliplatin) or gemcitabine (Gemzar®; Eli Lilly) + paclitaxel protein-bound particles (Abraxane®; Abraxis Biosciences/Celgene).

Novel approach
Now a new treatment option may offer better results for the treatment of patients with these hard to treat cancers.

The research of the scientists at Houston Methodist and The University of Texas MD Anderson Cancer Center in let to the creation of monoclonal antibody 130A to block the action of a protein called MFAP5 secreted by the cells surrounding and supporting ovarian and pancreatic tumor cells.

In a study, funded in part by the National Institute of Health (NIH), the University of Texas MD Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence, and others*, and published online July 22, 2019 in the journal Clinical Cancer Research (a journal of the American Association for Cancer Research), co-corresponding authors Stephen T.C. Wong, Ph.D., from Houston Methodist Cancer Center and Samuel Mok, Ph.D., from The University of Texas MD Anderson Cancer Center report that they have found a new type of immunotherapy to try in the fight against these two deadly malignancies. [1]

Wong, Mok, and colleagues developed a monoclonal antibody to block the action of a protein secreted by the cells surrounding and supporting tumors in ovarian and pancreatic cancers, called MFAP5. This protein is found at high levels in patients with both these cancers and associated with decreased survival rates.


The creation of monoclonal antibody 130A to block the action of a protein called MFAP5 secreted by the cells surrounding and supporting ovarian and pancreatic tumor cells.
The creation of monoclonal antibody 130A to block the action of a protein called MFAP5 secreted by the cells surrounding and supporting ovarian and pancreatic tumor cells.

“We found that blocking MFAP5 enhances the effectiveness of chemotherapy treatments and suppresses tumor growth in ovarian and pancreatic cancers, as well as inhibits progression of these two cancers in mice,” said Wong, who is also professor of computer science and bioengineering in oncology at the Houston Methodist Research Institute.

“This new immunotherapy drug targets supporting cells surrounding a tumor rather than just the tumor cells alone. This tumor microenvironment contains newly developed blood vessels and fibrous connective tissue – created through the processes of angiogenesis and fibrosis – that feed and support the tumor,” Wong added.

The MFAP5 protein has been shown to trigger the formation of these surrounding elements that supply and stimulate the tumor, influencing how it grows and spreads. Blocking it prevents new blood vessels and excess tissue from forming within the microenvironment, thereby cutting off the tumor’s blood supply and support.

“MFAP5 promotes fibrosis in ovarian and pancreatic cancers, and fibrosis promotes progression, chemo-resistance and reduces survival of people with these cancers,” explained Mok, who is an endowed professor of gynecologic oncology and reproductive medicine at MD Anderson.

“By blocking this secretory protein with an antibody, we can treat the tumor by targeting multiple cellular types – fibroblasts and blood vessels — in the tumor micro-environment,” he added.

Now that they have demonstrated the feasibility of using their monoclonal antibody to target MFAP5 as a new cancer treatment regimen, the researchers are in the process of designing and generating a humanized anti-MFAP5 antibody for further development as a therapeutic agent to treat ovarian and pancreatic cancers.

Wong said that they expect to have an anti-MFAP5 antibody ready by the end of the year for efficacy and toxicity testing, followed by a Phase I clinical trial in 2020.

“The convergence of biological science, computational science, and engineering has allowed us to achieve such translational discovery,” Wong concluded.


* The study was supported in part by grants from National Institute of Health (NIH), The University of Texas MD Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence,  the U.S. Department of Health and Human Services, the Ting Tsung and Wei Fong Chao Foundation, John S. Dunn Research Foundation, Gilder Foundation, the Ovarian Cancer Research Program, US Department of Defense and funding support from the Mary K. Chapman Foundation and the Ovarian Cancer Research Fund.

References
[1] Yeung TL, Leung CS, Yip KP, Sheng J, Vien L, Bover L, Birrer MJ, Wong STC, Mok SC. Anticancer immunotherapy by MFAP5 blockade inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer. Clin Cancer Res July 22 2019 DOI: 10.1158/1078-0432.CCR-19-0187 [Article]