BOSTON — The protein GP88 makes an excellent diagnostic for identifying tumors unresponsive to tamoxifen, while an anti-GP88 antibody shows promise as an anti-cancer therapeutic. This information raises the possibility of a promising theranostic, Ginette Serrero, president and chef scientific officer of A&G Pharmaceutical, said during the IBC Biomarker Pipeline conference, held here this week
Serrero's company is currently arranging to meet with the US Food and Drug Administration to discuss applying A&G's GP88 protein for FDA clearance as a biopsy-staining diagnostic, Serrero told Pharmacogenomics Reporter.
Two later products will measure serum, and screen more rapidly, she said. Once the diagnostic, called CancAlert, is on the market, it will produce demand for a second monoclonal anti-GP88 antibody that functions as a therapeutic, inhibiting GP88 function, Serrero said.
A&G's research is financed by its rapid, custom monoclonal antibody-manufacturing services, which cater to "large pharma," said Serrero.
More than $5 billion is spent on diagnostics for breast cancer in the United States annually, Serrero said during her presentation. One in seven women in the country is eventually diagnosed with breast cancer, but there is no systemic screen to detect the disease, and recurrence is usually detected by self-examination, she said.
If the disease is caught in its early stages, 97 percent of patients survive at least five years, compared to 21 percent for those who detect a tumor during the distant stage, she added.
While GP88 — known as autocrine growth factor — is needed by breast cancer cells, it is not produced or required by normal cells, said Serrero. According to A&G data presented at the conference, the protein is overexpressed in about 80 percent of breast cancer cells, compared to Her2, which is overexpressed in approximately 25 percent of these tumor cells.
In expression studies, A&G showed that an increase in GP88 tumor mRNA and secreted GP88 protein corresponded to increasing tumorogenicity, while inhibiting the gene with antisense RNA decreased the number and spread of tumors in nude mice.
But interestingly, GP88 overexpression seems tied directly to tamoxifen resistance — as compared to low-GP88 cells, cells overexpressing the protein grow nearly unimpeded while under treatment with the drug, said Serrero. "Does GP88 play a role in tamoxifen resistance? The answer is yes," she said. Not only are cells overexpressing GP88 more resistant to tamoxifen, they also show resistance to Herceptin and doxorubicin, she added.
A&G's first diagnostic product will be a GP88 biopsy staining kit that "predicts response to existing therapy," and can improve patient stratification, Serrero said. Her data for a group of 124 patients show a significant increase in GP88 as patient prognosis declines, raising the possibility that patients with high GP88 should receive more aggressive treatment, she said. The company's second diagnostic tests serum for an elevated level of GP88, which correlates closely with disease recurrence, Serrero said.
Ultimately, the company hopes its kits can be used as a regular part of the cancer-patient decision tree. Patients showing low GP88 can be treated with tamoxifen or Herceptin, depending on the results of an estrogen receptor test or a HercepTest, respectively. Should A&G's test reveal high levels of GP88, patients will be shunted toward chemotherapy, anti-GP88 therapy, or radiation treatment, according to the company's model.
— CW