August 08, 2014 by Azwad Rahman
Drexel College of Medicine researchers Alessandro Fatatis and Joseph Salvino have developed a compound that helps prevent the metastatic spread of certain cancers, such as breast cancer and prostate cancer. Metastatic cancers are cancers that find a way to spread from one organ to another, and many are incurable. They are currently developing a new version of the compound to prepare it for clinical trials.
Fatatis, a professor of the college’s Department of Pharmacology and Physiology, also holds a leadership position in the Sidney Kimmel Cancer Center at Thomas Jefferson University. His lab developed the compound and specializes in experimental oncology.
“We are particularly interested in the dissemination of solid tumors in prostate and breast cancers — these are tumors that are very effectively treated when they are locally confined, but when they disseminate, the problem for the patient really starts. And we focus on the mechanism that allows these cells to disseminate from the primary location to secondary, distant locations,” Fatatis said.
The dissemination — such as in the case of breast cancer — can occur when the cells infiltrate different types of vessels, such as blood or lymph vessels, and spread through the body.
“The entire research enterprise is based on cellular and molecular biology techniques, those that are done in the lab on the bench, and I would say a significant amount of work with animals,” Fatatis continued.
The compound, according to Fatatis, blocks a target protein named CX3CR1, which is located on the cellular surface. Cells use CX3CR1 to migrate and attach to other cells, including those lining the interior surfaces of blood vessels. This is called metastasis.
Breast and prostate cancer cells overexpress CX3CR1, and therefore have more on their cell surface than is normal and use it to invade the bone marrow from the blood circulation. In order to do this, the protein must interact with another unique molecule, but the compound blocks CX3CR1 from being able to interact with the other molecule.
“The [compound] really blocks the ability of cancer cells to reach the bone marrow and make a new home there because cancer cells, despite being malignant and very aggressive, are not very happy when they are floating [through the blood]. They are not meant to be floating. They are meant to be attaching to [other cells]. Without attaching, they can cope with it, [but] after 48 hours if they don’t find another way to attach, they die a natural death,” Fatatis said.
One of the potentials of these new compounds, according to Fatatis, is not only its ability to block metastasis, but it will also lack the adverse side affects that current cancer treatments have, such as chemotherapy, which kills normal cells as well as cancer cells.
The compound would not affect any processes such as immune responses, according to Fatatis, because studies that used genetically modified animals found that those that do not express the receptors have normal immune systems.
Fatatis had previously worked on the target protein on the cancer cells that his compound acts on years prior when he worked at the University of Chicago. In 2004, Fatatis published a study on the target protein of human prostate cancer cells titled “CX3CR1-Fractalkine Expression Regulates Cellular Mechanisms Involved in Adhesion, Migration, and Survival of Human Prostate Cancer Cells” and found that the target protein was a useful target. It wasn’t until 2010, however, that he started looking into acting on it.
Fatatis met Salvino, another professor of pharmacology, who had extensive experience in chemistry and explained his target. According to Fatatis, he asked Salvino if it was plausible to conceive a molecule against the protein, Salvino said yes, and they began working together.
“He came back two weeks later with a vial and it was a compound, the beginning of the story,” Fatatis said.
The two researchers continued testing different compounds until they found one that worked the way they wanted.
Fatatis said, “This was the compound that did it, because this was the compound that was working beautifully in the animals.”
Fatatis and Salvino then applied for many grants for their compound, including the National Cancer Institute’s highly selective Experimental Therapeutics Program. Also called NExT, the grant would allow them access to a network of facilities and investigators to take a compound from the lab into the clinic. The resources, according to Fatatis, ranged in worth from $5 to $6 million, and their compound was selected.
“That, for us, was more than money. It was just a true pat on the back from the NCI saying, ‘We think there is really something here,’” Fatatis said.
Through this program, Fatatis estimates that the compound will enter clinical trials in three to four years. The time between then and now will be used to perfect the compound, which is currently cardiotoxic to humans (poisonous to heart and heart functions). Salvino has already been developing new compounds that are seen as just as efficient as the current one in experimental models, without the cardiotoxicity.
“The idea is that every breast cancer patient is cured when the tumor is localized. We don’t lose one single breast cancer patient from the primary tumor. The primary tumor is always treated successfully, but if these cells are able to disseminate, the disease takes a wrong turn,” Fatatis said.
He continued, “What we are planning to do with this drug is not necessarily blocking the dissemination from the primary tumor to secondary sites because that might be done for patients with particularly aggressive tumors, but most importantly we are trying to target those patients that eventually develop metastatic disease. And we are talking about eight, 10, 12 percent of breast cancer patients.”
He believes that the drug should be used in combination with chemotherapy and other treatments.
Fatatis also explained that although blocking this dissemination process would prevent only around 60 percent of the cancer cells from attaching to the bone marrow, the other 40 percent had been unable to produce tumors in experimental models. Thus, patients who are treated with the compound would have fewer cancer cells disseminating and would be likely to have fewer tumors developing.
Along with solving issues specific to breast and prostate cancers, Fatatis predicts that this compound could also be applied to other types of cancers, such as ovarian cancer. However, due to the different ways that those cancers disseminate, adjustments need to be made to the compound.