Take TAT: HIV protein combats cancer

Laura Geggel

Imagine a molecule so small and sneaky that it can slip into a cancerous cell and deliver a trigger for cell death. The molecule, called TAT, has baffled scientists for a decade, and it comes from HIV.

TAT itself does not cause cell death. Gleaned from HIV’s protein envelope, this tiny molecule can drag entire viruses into cells. Researchers can produce stores of TAT (transactivator of transcription) by using protein synthesizers, but although they have decoded its genetic structure, they are unsure of exactly how TAT manages to bypass cell membranes.

“We still are at the very beginning of understanding how one protein from HIV is able to perform this amazing task of dragging much bigger molecules than itself inside the cell,” said William Hawkins, assistant professor of surgery at the medical school, Site Cancer Center member and senior writer for the study. TAT can tow molecules up to 1,000 times its size.

The idea for a cancer treatment involving TAT arose when Hawkins met with professor of anesthesiology Rich Hotchkiss, who was trying to use TAT to save cells from apoptosis, or cell death. Hawkins wondered if he could use TAT to destroy, instead of save, cells.

Hotchkiss had armed TAT with a domain of BIM, a regulator of the apoptotic pathway. Over-expression of BIM triggers a sequence of events that leads to cell death. If researchers can increase concentrations of BIM in specific cancerous cells, then tumors can be slowed or suppressed.

The paper, “TAT-Bim Induces Extensive Apoptosis in Cancer Cells,” published in January’s Annals of Surgical Oncology, is the beginning of a larger research project, said Research Instructor Jonathan McDunn.

“What we published so far is a demonstration that this growth helps slow the growth of a tumor. What we’re looking for now is combining that with other approaches to kill the tumor that then may work together,” he said.

Cancerous cells resist signals that tip the cell toward apoptosis. In pancreatic cancer, Hawkins’ area of expertise, cancerous cells over-regulate signals that protect the cell from suicide. Every day, millions of cells undergo self-directed death.

“Cells undergo death when they become too crowded. They undergo death when the immune system tells them to,” said Hawkins. “Cancers get signals that tell them to die because they’re too crowded, they run out of blood and sugar, and they ignore that and continue to grow.”

Hawkins and his crew contacted McDunn, who synthesized TAT with BIM to create the new cancer drug.

“Basically we’re telling the cancer cell that it has permission to go ahead and die and respond to these normal signals,” said Hawkins. Doctors can increase signals for cell suicide by prescribing chemotherapy or radiation.

Although Hawkins has concentrated on pancreatic cancer, he said there was no reason why the TAT-BIM drug could not be used on other types of cancer. The drug is still in the development phase and being tested on cell lines and mice, but clinical trials are not too far away.

“We take cancers from people, make cancer lines, and test the drugs first against those lines. You don’t want to use animals unless you know that your drugs are going to work against the cancer,” said Hawkins.

The research team of nine, all from Washington University, is planning next to publish a paper on how the TAT-BIM targets cancerous cells. By working with radiologists, they are using cancer-identifying molecules to hunt tumors.

“We’re hooking our molecules, which can get inside the cell, to molecules which know how to find cancer. With the combination of these multi-domain things, the molecules are able to find cancer, get into cancer, and leave normal tissues alone for the most part,” said Hawkins.

“Cancer has outwitted us for many years now. The reason we’ve made progress is because we have people from all different specialties that all get in a room and talk about things,” said Hawkins. “Here we are cancer doctors learning stuff from HIV doctors, and some of the newer molecules that we’re working on are from radiologists to label things for X-ray studies.”

Leave a Reply