Fox Chase-Temple Team Pursues a New Avenue in Transporter Membrane Proteins

TOPLINE

  • Researchers identified transporter membrane protein ABCC10 as a viable target in mammary tumors; next, they will test its potential as a target in lung tumors
  • A collaborative search for an optimized ABCC10 inhibitor is underway using molecular models

Because of their ability to carry drugs out of cells, affecting biological processes such as metastasis, migration, and proliferation, transporter membrane proteins have long been a focus in cancer research. For the last 30 years, much of the research in this area has focused on P-glycoprotein, or Pgp, but after many failed studies and clinical trials, research on Pgp has fallen out of favor. However, preliminary studies by researchers at Fox Chase have revealed another transporter membrane protein, ATP-binding cassette, subfamily C, member 10 (ABCC10), as a potentially more successful target for anti-cancer drugs.

A major limitation of inhibiting Pgp is that it causes other transporter membrane proteins to be induced, leading to increased toxicity and lethality. But Fox Chase researcher Elizabeth Hopper-Borge, PhD, found that inhibiting ABCC10, also known as MRP7, has the opposite effect—in some cases it downregulates other transporters and other proteins important to cell signaling pathways, leading to reduced drug resistance and a better response in tumors.

A molecular model of the protein ABCC10 with bound inhibitor. The protein is shown as a ribbon that follows along the protein chain, with the first half of the protein sequence colored in cyan and the second half in green. The atoms of the inhibitor are shown in magenta spheres.

A molecular model of the protein ABCC10 with bound inhibitor. The protein is shown as a ribbon that follows along the protein chain, with the first half of the protein sequence colored in cyan and the second half in green. The atoms of the inhibitor are shown in magenta spheres. Image by Roland Dunbrack

A study by Hopper-Borge and colleagues, published in the British Journal of Cancer in June 2014, examined whether inhibiting ABCC10 would make mice with mammary gland tumors more responsive to docetaxel, a taxane commonly used to treat breast cancer. The team bred ABCC10-negative and -positive mice to the common mammary tumor virus-polyomavirus middle T (MMTV-PyVmT) model, whose tumors are highly analogous to human breast tumors. They found that the loss of ABCC10 affected multiple biological parameters in the mice’s tumors, and increased their survival.

Studies of human lung cell lines in xenograft models showed similar biological effects to those seen with mouse mammary tumors. Hopper-Borge believes ABCC10 will prove to be an even better target in treating lung tumors, and her team is currently breeding mice to explore this theory.

“Our ultimate goal is to move this research into a clinical trial once we find an optimized compound,” Hopper-Borge says.

In pursuit of this compound, Hopper-Borge began working with Temple University organic chemist Rodrigo Andrade, PhD, who tested existing novel inhibitors against ABCC10 and found that the results were effective—further confirming ABCC10’s viability.

Next, they teamed up with Fox Chase researcher Roland Dunbrack, PhD, who specializes in protein structure prediction. Using experimental data Hopper-Borge gathered while testing a preliminary compound that Andrade created, Dunbrack will develop models to predict whether and how a compound will bind to ABCC10—yielding information about how to strengthen the compound.

“We’re still learning a lot,” Hopper-Borge says, “but renewed interest in transporter membrane proteins is certainly starting to gain momentum.”

Elizabeth Hopper-Borge-PhD

Elizabeth Hopper-Borge, PhD

Hopper-Borge’s co-authors include Natalya Domanitskaya, PhD, Janet Wangari-Talbot, PhD, Joely Jacobs, Elizabeth Peiffer, Chelsy Paulose, Ekaterina Malofeeva, PhD, Katherine Foster, Kathy Q. Cai, MD, PhD, Yan Zhou, MSE, PhD, and Brian L. Egleston, PhD.