Researchers from the Higher Council for Scientific Research (CSIC) have demonstrated the in vitro and in vivo efficacy of a treatment for a type of breast cancer, known as HER2 positiveresistant to first- and second-line drugs, such as T-DM1a modified antibody used to treat HER2-positive tumors.
Despite its effectiveness, in advanced stages of the disease, this drug may stop working. “We have begun to study other possibilities of treating HER2-positive breast tumors when tumor cells resist T-DM1«, points out Atanasio Pandiella, a CSIC researcher at the Cancer Research Center (CIC-CSIC-USAL). »We have identified why some cells that originally have the HER2 protein become resistant to T-DM1. Cells resistant to this treatment have lost HER2 expression. We have found that the treatment is no longer effective because these resistant cells do not have the antibody target, while the tumor cells that continue to express HER2 die with T-DM1″, added Pandiella.
The work, published in the journal ‘Cancer Letters’, has identified a new target that can be acted on by a targeted antibody.
Since the drug T-DM1 cannot be effective when there is loss of HER2 in certain tumor cells, if they are not acted on, breast cancer continues to progress. Therefore, it is necessary to find other treatment alternatives for these cases of resistance.
Pandiella’s team has selected a cell surface protein called EGFR, which is present in the membrane of resistant cells. “Since EGFR is in these cells, we have developed in our laboratory a modified antibody of the ADC type (drug-conjugated antibody) against EGFR and analyzed its effect. And indeed we have verified that the ADC against EGFR had an antitumor action”, explains the researcher.
The naked antibody used to develop this new drug is commercial, however, the laboratory has made the ADC by adding a cytotoxic drug to said antibody.
“We in the laboratory are studying why certain cells can develop resistance to a treatment and we are looking for new strategies to address this resistance. From here on, it must be clinicians or the pharmaceutical industry that continue with clinical trials“, says Pandiella.
ADCs represent a sophistication of antitumor antibodies. For an ADC to work, it is necessary for the tumor cell to contain the protein recognized by the drug. Antibodies conjugated to drugs maintain the antitumor activity of the antibody, but in addition a drug that is highly toxic to the tumor cell is included. This way, drug is released only in tumor cells and it does not affect healthy cells, thus reducing the toxicity of the treatment and increasing its effectiveness. There are currently HER2-positive breast cancer treatments based on ADCs, which attack the HER2-positive tumor cell more strongly.
In this sense, in 2013 the drug T-DM1 was approved as a single agent by the US (FDA, on February 22) and European (EMA, on November 15) agencies, for the treatment of adult patients with HER2 breast cancer. advanced positive who have previously received trastuzumab and a taxane, separately or in combination. This drug, T-DM1, is prescribed when the person has developed a resistance to conventional breast cancer treatments. If a drug ceases to be effective as a first alternative for the treatment of cancer, it is passed to second-line drugs.
T-DM1 is a second-line drug for the treatment of HER2-positive breast cancer. It is composed of the anti-HER2 antibody trastuzumab (Herceptin®), and the antimicrotubule cytotoxic agent DM1, linked by a stable bond. Therefore, this drug acts on the microtubules of the cell, which are essential for the cell to divide. The results of T-DM1 are very good. However, some patients also stop responding to this second-line drug over time. And the Cancer Research Center has identified one of the causes of this resistance.