Research team determined to improve the prognosis of invasive triple breast cancer

Principal Investigators believe “the consortium as a whole will benefit from this international collaboration, involving multidisciplinary and complementary teams”.

In 2017, the UT Austin Portugal Program opened a call for Exploratory Research Projects (ERP), funded by FCT. The goal was to promote and finance short-term exploratory scientific projects proposed by teams of experts and researchers targeting strategic areas of the program. NANOTHER was one of the awarded projects.

Led by Manuel Bañobre, from the International Iberian Nanotechnology Laboratory (INL), and Zhengrong Cui from University of Austin at Texas (UT Austin), NANOTHER is the acronym for “Targeted and externally controlled nanotheranostics of triple-negative-breast-cancer”. The consortium brings together UT Austin, UMinho and INL, each with different complementary skills, background knowledge, expertise and research/training environments.

In an interview with both Principal Investigators, we learned more about the current prognosis, facts, figures and the work that is being conducted towards a more beneficial intervention for patients with this type of cancer.

What is the current prognosis for triple-negative breast cancer and how common is this form of cancer?

Triple-negative breast cancer (TNBC) represents 20% of the 3 million new cases of breast cancer diagnosed in women worldwide every year. In Portugal, the incidence of breast cancer is of 118.5 women per 100000 population (2010, Registo Oncológico Nacional), which represents 30% of the newly diagnosed cancer cases in women every year and still shows a mortality index of 18%. Compared to other types of breast cancer, TNBC is more aggressive and has a poorer prognosis. Targeted therapy is not available for TNBC because this subtype of breast cancer lacks the expression of ER, PR and HER2. Furthermore, TNBC often is among the highest-grade breast cancers. The only systemic therapy currently available for patients with TNBC is adjuvant chemotherapy with anthracyclines (e.g., doxorubicin), taxanes (e.g., paclitaxel), or cyclophosphamide. However, the response to the treatment is far from ideal.

High rates of relapse, in addition to low survival rates in patients with residual disease after treatment, are observed. Therefore, the lack of targeted therapeutic options, the limited efficacy of current treatments, together with the well-known adverse effects of chemotherapy, demand an urgent effort to discover specific targets and develop novel targeted therapies as well as early diagnostic methods.

So what you are proposing is the development of what can possibly contribute to a new form of therapeutic intervention in patients with TNBC, in the future. Can you explain a little better the research work you will be conducting throughout the year?

Recent advances in nanotechnology have shown high promise for targeted delivery of personalized treatment with natural and engineered nanomaterials. The main objective of this project is to ameliorate the prognosis of TNBC through the preparation and preclinical validation (in vitro plus in vivo) of a targeted theranostic nanoparticle/probe that is able to specifically recognize tumor-associated macrophages (TAMs), offering a non-invasive imaging capability by MRI together with a synergic magnetic hyperthermia and chemotherapy treatment against TNBC. To achieve this goal, lipid-based nanoparticles will be loaded simultaneously with magnetic nanoparticles and an anticancer drug. As a result of the induced magnetic functionality, the resulting hybrid nanoparticles will behave as T2-contrast agents in magnetic resonance imaging (MRI) and enable a magnetic hyperthermia (MH)-mediated controlled drug delivery, in addition to the localized thermal damage. In order to promote the active targeting of the theranostic probe in the tumor area and overcome one of current limitations of MH-based therapy, the hybrid nanoparticles will be surface-functionalized to target TAMs. At the end of the funding period, we expect to have an in vitro and in vivo validated theranostic probe showing imaging and multi-treatment capabilities against TNBC. These expected results will enable future translational research and will be the key in the advance towards an adequate and timely therapeutic intervention in patients with TNBC, being also a step forward on the way to targeted, image-guided therapies of cancer.

This is a very ambitious project. What challenges do you expect to face moving forward?

The whole project is a challenge in itself. Nowadays, imaging and therapy methodologies are independently applied in the clinics. The use of theranostic probes combining both properties in one single platform will open new opportunities, for example, in the monitoring of the response to treatment of different diseases, cancer in particular. One of the main challenges is the complex engineering of these multifunctional probes, which involves the chemical assembly of several previously synthesized raw materials and ligands. In addition, triple-negative breast cancer cells are difficult to target because they do not express PR, ER, and HER2. To solve this problem, we propose to exploit TAMs as a target (instead to the tumor cells), since in breast tumors, TAMs represent up to 50% of the total mass of the tumor tissue.

The NANOTHER project has assembled a cross-disciplinary research team with expertise in different fields. Can you tell us a little more about the complementarity of skills and resources you have gathered in both sides of the Atlantic?

The development and validation of a new theranostic agent that has the potential of providing diagnosis capability by MRI and targeted therapeutic action against TNBC involve a series of multidisciplinary scientific tasks and challenges that certainly call for a translational cooperation approach. Two main areas of research are represented herein, namely nanomaterials chemistry and pharmaceutical technology. The intimate combination of these two disciplines will result in a synergy to develop basic research into tangible innovative applications. Therefore, chemists, biochemists, biologists and pharmaceutical scientists are required to closely collaborate during the whole timeline of the project. On one hand, Dr. Bañobre’s team at INL (AmTheNa Lab) has strong expertise in the synthesis, characterization and functional validation of magnetic nanocomposites for application in biomedicine, whereas the group of Prof. Baltazar at UMinho is specialized in cancer metabolism and the use of human tumor samples and suitable models for in vitro and in vivo studies. Moreover, the advanced physicochemical characterization techniques and unique state-of-art equipment available at INL will provide the whole consortium invaluable means to optimize the theranostic performance of the designed theranostic platform. On the other hand, the team of Prof. Cui at UT Austin has the materials needed to surface-functionalize the nanoparticles and is experienced in the in vitro and in vivo validation of a wide range of pharmaceutical formulations with unconventional targeting and therapeutic properties. The whole project will benefit from the in vivo capability of UT Austin. The consortium as a whole will benefit from this international collaboration, involving multidisciplinary and complementary teams in the fields of nanomaterials and biomedical research.

The Exploratory Research Projects have a duration of 12 months. What conclusions are you expecting to reach after hitting the one-year mark?

This proposal contributes to addressing a significant challenge in the area of health, and bridging the gap identified between fundamental and applied sciences through the design of in vitro and in vivo validation tests for the synthesized theranostic probes. This initiative represents an innovative and groundbreaking use of tailored hybrid nanocomposites as an innovative and tangible solution in the field of targeted drug delivery against cancer, TNBC in particular. Imaging and externally controlled drug delivery capabilities, in combination with magnetic hyperthermia and active targeting, will be integrated in one single platform. The expected scientific advances will contribute to the ultimate clinical translation and a wide-range of innovations with potential to impact TNBC therapy.