New Anti-cancer Drug: 200 Times More Active In Killing Tumor Cells

A team of 24 researchers from the U.S., Europe, Taiwan and Japan and led by University of Illinois scientists has engineered a new anti-cancer agent that is about 200 times more active in killing tumor cells than similar drugs used in recent clinical trials.he study appears this week in the Journal of the American Chemical Society.

The new agent belongs to a class of drugs called bisphosphonates. These compounds were originally developed to treat osteoporosis and other bone diseases, but were recently found to also have potent anti-cancer and immune boosting properties.

Drug developers have tried for years to design drugs to inhibit cell survival pathways in tumor cells, focusing on a protein called Ras since nearly a third of all human cancers involve a mutation in the Ras gene that causes cell signaling to go awry. These efforts have met with limited success.

Bisphosphonates act on other enzymes, called FPPS and GGPPS, which are upstream of Ras in the cell survival pathway. Inhibiting these enzymes appears to be a more effective strategy for killing cancer cells.

When used in combination with hormone therapy in a recent clinical trial, the bisphosphonate drug zoledronate significantly reduced the recurrence of breast cancer in premenopausal women with estrogen-receptor-positive breast cancer. Similar results were reported previously for hormone-refractory prostate cancer.

But zoledronate quickly binds to bone, reducing its efficacy in other tissues.

"We're trying to develop bisphosphonates that will be very active but won't bind to the bone, because if they bind to the bone they're not going to go to breast, lung or other tissues," said University of Illinois chemistry professor Eric Oldfield, who led the new study.

Oldfield's team also wanted to design a compound that would inhibit multiple enzymes in the tumor cell survival pathway, rather than just one, an approach analogous to the use of multi-kinase inhibitors in cancer therapy.

Andrew Wang, of Academia Sinica, Taipei, and Illinois chemist Rong Cao began by producing crystallographic structures of the target enzymes and drug candidates, allowing the researchers to identify those features that would enhance the drugs' ability to bind to the enzymes. Using this and other chemical data, Illinois chemistry department research scientist Yonghui Zhang engineered new bisphosphonate compounds that bound tightly to multiple enzyme targets, but not to bone.

One of the new compounds, called BPH-715, proved to be especially potent in cell culture and effectively inhibited tumor cell growth and invasiveness.

Tadahiko Kubo, of Hiroshima University, then found that BPH-715 also killed tumor cells in mice. And Socrates Papapoulos, of Leiden University, the Netherlands, showed that the compound had a very low chemical affinity for bone.

In humans, compounds like BPH-715 and zoledronate have an added benefit in fighting cancer: They spur the proliferation of immune cells called gamma delta T-cells, which aid in killing tumor cells.

"The new drugs are about 200 times more effective than the drugs used in recent clinical trials at killing tumor cells and in activating gamma delta T-cells to kill tumor cells," Oldfield said. "They also prevent tumor progression in mice much better than do existing bisphosphonate molecules."

World’s First Successful ViKY Robot-assisted Surgery For Pancreatic Tumors

This month Fox Chase Cancer Center performed the world's first successful minimally invasive distal pancreatectomy using the ViKY® system's revolutionary robotic, compact laparoscope holder. The technology, developed in France and tested on thousands of patients in Europe, made its debut in a cancer setting in the United States at Fox Chase. "Fox Chase is among only a handful of institutions worldwide using robotics or laparoscopy to treat patients with nearly all types of cancer," says Robert G. Uzzo, MD, FACS, chairman of the department of surgery at Fox Chase. "The use of technology, like the ViKY system, reinforces our Center's commitment to excellence in minimally invasive surgical techniques for the care of patients with both benign and cancerous conditions."

Fox Chase surgeon Andrew A. Gumbs, MD, who specializes in minimally invasive hepato-pancreatic and biliary (HPB) surgery, explains, "This system is so versatile that surgeons like me are able to use it for many different laparoscopic procedures, including those in the gastrointestinal, urologic, thoracic and gynecologic regions."

Typically with minimally invasive procedures, like a laparoscopic distal pancreatectomy, surgeons use both hands to manipulate the surgical tools and need an assistant to manipulate the endoscope—a thin, lighted tube equipped with a camera that allows the surgeon to view the surgical field.

Gumbs performed this first ever ViKY assisted minimally invasive distal pancreatectomy on a 65-year-old man who was diagnosed with two pancreatic cysts, one of which is potentially cancerous. Pathologists are currently evaluating the cyst.

"The new ViKY robotic laparoscope holder acts as an extra hand during surgery, giving me stability and steadiness," adds Gumbs. "The view of the surgical field is critical, so ViKY's pinpoint accuracy helps me perform more complex procedures laparoscopically." Unlike typical laparoscope holders, the ViKY system's holder is lightweight, easy to set up and use, and takes no floor space.

Standard treatment for pancreatic cancer is surgery to remove the head or tail of the pancreas. When patients present with pancreatic cancer localized to the tail of the pancreas (instead of the head), they undergo a distal pancreatectomy, in which the surgeon removes the tail of the pancreas and leaves the head attached. The remaining portion can function normally by producing and releasing digestive enzymes and hormones. Patients with pancreatic cancer are typically treated with surgery followed by radiation therapy and/or chemotherapy to reduce the risk of recurrence.

The ViKY system gave Gumbs precise control of the laparoscope while he performed the distal pancreatectomy. The endoscope moves according to the surgeon's orders, either through voice recognition or footswitch control.

Before the ViKY technology was available patients might have undergone open surgery. Depending on the complexity of the case, the surgeon may have considered open abdominal surgery, requiring a large incision and a lengthy recovery. Minimally invasive surgical techniques, like the surgery Dr. Gumbs performed, benefit patients in many ways, including a shorter hospital stay, faster recovery, quicker return to daily activity, less risk of infection and less scarring and bleeding.

Gumbs was the first American surgeon to complete a minimally invasive HPB fellowship at the Institut Mutualiste Montsouris in Paris, France. This is the hospital where the first published case of a single incision laparoscopic cholecystectomy in the world was done using the ViKY system. Gumbs is responsible for bringing the ViKY system to Fox Chase and will be training fellow surgeons on this technology.

The ViKY system is manufactured by Endocontrol Medical in La Tronche, France. Endocontrol is an innovative company offering robotic solutions for endoscopic surgeries. Endocontrol was created by Clement Vidal and Patrick Henri of Joseph Fourier University, Grenoble, France, a worldwide leader in computer assisted and robotic surgery.