• A new strategy has been developed to make it possible to identify tumor cell membrane proteins, in order to later specifically attack these cells using specific antibodies against these proteins.
• This work lays the groundwork for defining new potential targets of drug-conjugated antibodies in other solid or hematological tumors.
• The research has been directed by Juan Carlos Montero (Cancer Research Center-IBSAL-University Clinical Hospital of Salamanca) and Atanasio Pandiella (Cancer Research Center, University of Salamanca-CSIC), both belonging to the Cancer CIBER (CIBERONC). The study has received funding from CRIS Contra el Cancer.
According to data published by the Spanish Society of Medical Oncology, the most diagnosed cancer in women is breast cancer. Although each patient’s tumor is molecularly different, clinically breast tumors are grouped into three subgroups. Among them, the so-called triple negative subtype is the most aggressive and represents 15-20% of all cases of breast cancer. Despite having different therapeutic options, these are still not enough to cure patients. Therefore, this type of breast cancer requires the incorporation of new and effective treatments into the clinic.
In this sense, a strategy that is giving good results is based on discovering new therapeutic targets in cancer by analyzing what is called the “surfaceome”, which are cell surface proteins. These proteins are being investigated because, due to their location on the cell surface, they are accessible, and the expression of some of them is altered in various types of cancer. In fact, some of these proteins are “overexpressed”, that is, their quantity is much higher in the tumor cell than in a normal cell. This allows us to preferentially act on the tumor cell using, for example, specific antibodies against that protein. There are currently different therapeutic strategies that target cell surface proteins. These include drug-conjugated antibodies (ADCs). ADCs are antibodies to which an agent toxic to the cell has been attached. Therefore, these drugs add the antitumor effect of the antibody and the antitumor effect of the drug attached to them.
“Taking into account the current need to incorporate new drugs aimed at triple negative breast cancer that are more effective and due to the clinical efficacy of ADCs – highlights the researcher, responsible for the work, Juan Carlos Montero, our group set out to identify new targets for ADCs that could be used to treat this subtype of breast cancer”. In the first place, a list of possible targets of the cell surface susceptible to be attacked with ADCs was elaborated. Specifically, using genomic and proteomic techniques, normal breast tissues and triple negative breast tumor tissues were compared. This study led to the identification of a group of about 20 proteins that could be targets of ADCs. Subsequent studies focused interest on one of them, called CD98hc. Against this protein, a drug-conjugated antibody (ADC) was prepared in the laboratory.
In the next phase of the research, in vitro experiments were carried out, that is, triple negative breast cancer cell lines were used. “In these studies it was observed – says Juan Carlos Montero – that this ADC had a powerful and specific antitumor activity against triple negative breast cancer cells”. The ADC against the CD98hc protein not only blocked cell cycle progression (it prevented tumor cells from expanding), but also ultimately caused tumor cell death.
To delve into the observed antitumor effect of ADC against CD98hc, new experiments were carried out. On this occasion, we worked with in vivo experimental models, that is, this antitumor effect of the CD98hc ADC was verified in mice with tumors created in them after injecting them with triple-negative human breast cancer cells. In this way, it was found that the ADC against the CD98hc protein reduced the tumor volume in the animal.
In short, highlights Pandiella, “these preclinical results open the door to the possibility of exploring the efficacy of ADCs directed against CD98hc in the clinic.” On the other hand, it is possible that the CD98hc protein is also overexpressed in other types of tumors. If this were the case, it would further extend the value of this work, as it would open the possibility of using the CD98hc protein as a new therapeutic ADC target for the therapy of other types of cancer. Finally, the use of this strategy to identify cell surface proteins differentially expressed in tumors, allows establishing the bases to define new potential targets of ADCs in other solid or hematological tumors.
The work has been carried out by researchers from the laboratory directed by Pandiella, the Cancer Research Center and the Pathological Anatomy Service of the University Hospital of Salamanca. Dr. Alberto Ocaña from the San Carlos Clinical Hospital in Madrid has also collaborated in the work.
The study has received funding from the Carlos III Health Institute, the Ministry of Science and Innovation, the Ministry of Education of the Junta de Castilla y León, and private entities (CRIS Contra el Cancer, UCCTA, ALMOM, ACMUMA).
J Exp Clin Cancer Res https://pubmed.ncbi.nlm.nih.gov/35317825/ doi: 10.1186/s13046-022-02330-4
2022 Mar 22;41(1):106. doi: 10.1186/s13046-022-02330-4.
Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
Juan Carlos Montero, Elisa Calvo-Jiménez, Sofía Del Carmen, Mar Abad, Alberto Ocaña, Atanasio Pandiella