Doctoral research network to study small molecule-drug conjugates for cancer treatment
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Doctoral researchers from 11 European institutions and four companies have formed a research network dedicated to developing molecules that stimulate the immune response to tumor cells.
The network, “Magicbullet::reloaded,” consists of 15 doctoral researchers from organic and medicinal chemistry, tumor biology and pharmacology. The researchers plan to conduct studies in this network through 2024.
“The inspiration for the network is reflected in its name; the first part refers to a term coined by Nobel laureate Paul Ehrlich, PhD, which defines an ideal therapeutic agent that would only target cancer cells sparing healthy tissues,” Lydia Bisbal Lopez, a PhD student at University of Milan, said. “That is precisely the goal of our network — to develop new constructs that will be more efficient than current cancer therapies, avoiding their major drawbacks.”
To develop these minimally invasive, targeted agents, the researchers attach a substance to transporter molecules, and the substance stimulates an immune response in tumor cells.
Norbert Sewald, PhD, a professor of organic and bioorganic chemistry at Bielefeld University in Germany, serves as the network coordinator.
Bisbal Lopez and her colleague Sveva Colombo, a PhD student in Sewald’s laboratory at Bielefeld University, spoke with Healio about the network’s approach to advancing new, more targeted cancer drugs.
Healio: What inspired the creation of this doctoral research network and what are its goals?
Colombo: The main objective is to research and synthesize anticancer molecules that can improve the future for patients, avoiding the collateral damage and consequent psychological state that chemotherapy produces.
Healio: How does your team attach a substance that damages tumor tissues to a transporter molecule? How does this work to treat cancer?
Bisbal Lopez: First, a transporter molecule or biological entity that targets cancer cells needs to be identified. Then, a cytotoxic drug has to be selected either from the literature or through a campaign whose aim is to screen different compounds and find the most potent one. Finally, a suitable linker has to be found to connect both parts. After the synthesis of the constructs, the key part involves in vitro and in vivo testing.
Colombo: Our goal is to obtain drugs that will kill only the “bad” cells and not harm the healthy ones. To do so, we have two possible strategies: to conjugate our killer compound through a linker to another molecule, producing a so-called small molecule-drug conjugate (SMDC), or to an antibody that is a protein already existing in our body, producing an antibody-drug conjugate (ADC). This is achieved either through chemical or biologic reactions. These molecules have a part called targeting moiety that can recognize the diseased cells. This part was chosen because as soon as it enters the body and passes close to a cell, the receptor on the cell surface grabs it. At this point, the conjugate can enter the cell and the killer part can be left free to do its job.
Healio: How does this process prevent resistance to immunotherapy? Has it been effective?
Bisbal Lopez: The targeted delivery of immunostimulatory compounds at the tumor site is used to promote a pro-inflammatory environment, which is associated with good prognosis, as well as better therapeutic efficacy of immunotherapy regimens.
Colombo: Immunotherapy has transformed the way many cancers are treated. Despite the great progress made, a substantial proportion of patients do not respond effectively to treatments. One strategy could be to administer molecules capable of determining modifications in the DNA of tumor cells in order to modulate their gene expression. Tumor cells are altered by this medication, which results in the expression of molecules on their surface that is crucial for the interaction between the tumor and the immune system. As a result, the tumor is more visible to the eyes of our defense cells. In this approach, ideal circumstances are produced so that immunotherapies can work more effectively.
Healio: What do you expect to be the long-term implications of your research? How might it impact clinical practice in the future?
Bisbal Lopez: We are working on finding new selective delivery systems of pharmaceutical active compounds for cancer therapy, and if they are successful they could potentially be used in preclinical studies. If these would also show positive results, our contribution to the research field would be translated directly into the clinic.
Colombo: We hope that some of the anticancer products will then be able to move on to increasingly advanced stages of testing. The idea is that this research could then one day, hopefully sooner, materialize into a marketed anticancer drug, and therefore that could benefit sick patients.
Healio: What are some other key aspects of the network’s research?
Bisbal Lopez: As the name of the network suggests, one of its characteristics is the strong collaboration between all beneficiaries, from the supervisors to the PhD students. We are a very interdisciplinary group, and very often new projects develop between biologists and chemists to bring our research forward.
Colombo: We are focused on the possibility of meeting and exchanging ideas and suggestions with people from various countries of the world to learn new things, and above all the possibility that biologists and chemists collaborate directly.
For more information:
Sveva Colombo can be reached at sveva.colombo@uni-bielefeld.de.
Lydia Bisbal Lopez can be reached at lydia.bisbal@unimi.it.
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