Ovarian cancer is the fifth leading cause of cancer death among women. Tumors often remain silent until they have spread; as a result, many women go undiagnosed until the disease has already advanced. Ovarian cancer cells often develop resistance to chemotherapy with taxanes and platinum agents, leaving few therapeutic options for women with advanced disease.
Two small peptides could present a new approach to ovarian cancer and potentially other tumors. Derived from a naturally-occurring human protein, they forced tumors to shrink significantly in an animal model of metastatic ovarian cancer, report researchers from Boston Children’s Hospital’s Vascular Biology Program, the University of Bergen and Weill Cornell Medical College in Science Translational Medicine last week.
Dubbed “psaptides,” the two peptides stimulate a response that targets tumor cells directly and also acts on nearby tissues to make the tumors’ immediate environment inhospitable to metastasis.
“Our goal is to develop treatments that that will cure people without making them more ill,” says senior author Randolph Watnick, PhD, of Boston Children’s. “We want to find a way to treat people with cancer without having to rely on cocktails of cytotoxic drugs that have significant side effects.”
Targeting both the tumor and its environment
For the last dozen years, Watnick’s laboratory has attempted to understand and manipulate the microenvironment in which tumors, in particular metastatic tumors, grow and thrive. In 2009, they announced that a protein called prosaposin (psap) could block metastasis in animal models of breast and prostate cancer. Prosaposin stimulates immune cells called monocytes to produce thrombospondin-1 (TSP-1), a potent anti-angiogenic and anti-inflammatory protein that makes otherwise-permissive tissues resistant to metastasis.
In 2013, together with collaborators Lars Akslen, MD, PhD, from the University of Bergen and Vivek Mittal, PhD, of Weill Cornell, Watnick showed that psaptide, a five-amino acid fragment of prosaposin, is fully capable of triggering TSP-1 production. The peptide significantly reduced metastatic spread in mouse models of prostate, breast and lung cancer.
In their current study, Watnick, Akslen and Mittal — with co-first authors Suming Wang, PhD, and Anna Blois, PhD, of Boston Children’s, and Tina El Rayes, PhD, of Weill Cornell — studied two modified, potentially enhanced versions of psaptide: D-psaptide and cyclopsaptide. Could they act on TSP-1 to force established metastatic tumors to regress?
That’s a two-part question and answer — but yes.
The team first found that D-psaptide and cyclopsaptide are, respectively, three and six times more potent than native psaptide at stimulating monocytes to release TSP-1.
But second, could these modified peptides eliminate ovarian tumors? Theoretically, they should: Ovarian cancer cells carry a receptor for TSP-1 called CD36 that, when triggered, can force ovarian cancer cells to enter apoptosis, or programmed cell death.
“Essentially, we’re using the prosaposin peptides as immunomodulators by getting them to turn monocytes into delivery vehicles to get TSP-1 to ovarian tumors,” Watnick explains. “This strategy should work without interfering with any immune response directed specifically against the tumor.”
Psaptides as peptide drugs for cancer?
The group next measured the peptides’ anti-tumor effects in a mouse model of ovarian cancer, which incorporates patient-derived tumor cells.
In one set of experiments, mice received daily treatment with cisplatin or D-psaptide for up to 83 days. In the second set, the tumors were allowed to establish themselves for a longer period of time and then were treated daily with either cisplatin or cyclopsaptide and followed for a shorter period (15 days) to allow close examination of any remaining tumor.
The results were striking. In the cisplatin/D-psaptide comparisons, tumors regressed in the cisplatin-treated mice until about day 20, but then became resistant and started growing again. Tumors in the D-psaptide-treated mice, by contrast, regressed and by day 48 were undetectable — and remained so until the end of the experiment 35 days later.
In the cisplatin/cyclopsaptide comparison, metastatic tumors in cyclopsaptide-treated animals were 2.3 times smaller than those in cisplatin-treated animals at the end of 15 days. TSP-1 was widespread in the tissue surrounding the tumors in the cyclopsaptide mice but nearly undetectable in the cisplatin mice. Finally, 59 percent of the cells in the cyclopsaptide animals’ tumors were apoptotic, compared to 11 percent in the cisplatin-treated animals.
Taken together, the study’s data form a strong body of evidence favoring exploration of psaptide-based peptide drugs.
“Many other tumors besides ovarian cancer express TSP-1’s receptor, CD36,” says Watnick, who has established a biotechnology company, Vigeo Therapeutics, to further develop the psaptides’ therapeutic potential. “It’s a key receptor for tumor cell growth, and if anything, they express more of it as they become more aggressive. Hopefully we can turn that dependency against them.”
The study was supported by the National Cancer Institute (grant numbers R01CA135417, P50CA083636, U01CA152990, R21CA156021 and U54CA143876) and Norwegian Research Council, the Norwegian Cancer Society, the Cornell Center on the Microenvironment and Metastasis, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Honorable Tina Brozman Foundation, the Robert I. Goldman Foundation, the Elsa U. Pardee Foundation, Boston Children’s Hospital’s Technology Development Fund and the Vascular Biology Program at Boston Children’s Hospital.
Wang S, Blois A, El Rayes T, Liu JF, Hirsch MS, Gravdal K, Palakurthi S, Bielenberg DR, Akslen LA, Drapkin R, Mittal V, & Watnick RS (2016). Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Science Translational Medicine, 8 (329) PMID: 26962158