“I didn’t know 99% of the other Oncode Investigators when I joined Oncode Institute in 2019” says Oncode Investigator Laura Heitman. That is because her research, focusing on drug-receptor interactions, occupies an extraordinary and rather new position in the landscape of oncological research.
Oncode Investigator and professor of molecular pharmacology at the Leiden Academic Centre for Drug Research (LACDR).
A pharmacological toolbox to target cancer-driving receptors
Heitman is a professor of molecular pharmacology at the Leiden Academic Centre for Drug Research (LACDR). “Making medicines work better; that is my aim. My research group studies G protein-coupled receptors – GPCRs. These are located in cell membranes, and they play a role in practically all physiological functions of our bodies. GPCR dysregulation is associated with a variety of diseases, including type 2 diabetes, hypertension, heart failure, and Alzheimer’s disease. GPCRs are the most exploited class of drug targets: more than thirty per cent of all drugs act on them”, says Heitman.
GPCRs were off the radars of cancer researchers for a long time, but it has recently become clear that some of these receptors play a role in tumour growth and metastasis. Heitman: “GPCRs appear to be involved in cancer progression in two ways. First, GPCRs on tumour cells may help the cells to proliferate and metastasize. Second, GPCRs on immune cells in the local environment of the tumour may suppress the patient’s immune system, preventing it from adequately taking care of the tumour. This dual role – on tumour cells and on immune cells – makes GPCRs interesting drug targets. Pharmacological manipulation of GPCRs may be a promising strategy to inhibit tumour progression and metastasis.”
"This dual role – on tumour cells and on immune cells – makes GPCRs interesting drug targets."
Although this sounds promising, the molecular knowledge about the role of GPCRs in cancer is very incomplete, hampering efficient drug development. GPCR activity can be altered in cancer through several mechanisms: (i) tumour cells may produce abnormally large amounts of these receptors, (ii) they may produce receptors with an abnormal structure due to mutations, and (iii) they may produce abnormally high amounts of agonists. (An agonist is a chemical that activates a receptor; an antagonist tempers the effect of an agonist.) Heitman and her team members study the interaction between GPCRs and their agonists, and they explore ways to manipulate this interaction with chemical compounds.
“The nice thing about GPCRs is that so many drugs act on them. Hence, many agonists and antagonists are commercially available. We can use these chemical compounds as tools to see which type of compound is the most efficacious in laboratory experiments. Ideally, we would like to develop a pharmacological toolbox to manipulate GPCRs: you open a drawer and pick the type of compound that best suits the tumour that you want to target. This may be a traditional agonist or antagonist, but in fact, my research group is mainly focusing on novel concepts in drug discovery” says Heitman.
“This is important because tumours often produce high concentrations of the agonist for GPCRs expressed in the tumour cells. So, we need compounds that can overcome the high concentration of agonist that is floating around in the tumour environment. This can be achieved with several novel concepts. The first is ‘allosteric modulation’. Allosteric modulators do not compete with the agonist, but rather bind to the receptor at a different site and inhibit it from there. Another novel concept is to use antagonists that bind to the GPCR for a prolonged period (‘long residence time antagonists’ or ‘covalent antagonists’). And recently, Natalia Ortiz Zacarías, a postdoc in my lab, has started looking into compounds that degrade GPCRs rather than inhibiting them” she explains.
“Yes, I am currently developing novel cellular assays to measure degradation of these receptors. In general, I am running different kinds of experiments, mostly cellular and membrane-based assays” says Ortiz Zacarías. “The chemokine receptor type 2 is my focus. This is a GPCR that is expressed in immune cells and may be involved in the immune response against tumours. I test various types of chemical compounds to study their mechanism of action, and to find out whether we can develop them into drugs that efficiently target chemokine receptors. Although I focus on the chemokine receptor type 2, my discoveries can be applied to many other GPCRs.”
Marina Gorostiola Gonzalez, Laura Heitman, Natalia Ortiz Zacarías
Like Heitman, Ortiz Zacarías is a biopharmaceutical scientist by training. The Heitman Lab is composed of scientists with complementary expertise, ranging from molecular biology, to pharmacology, organic chemistry, and computational modelling. The latter is the expertise of Marina Gorostiola Gonzalez, a PhD student that is co-supervised by Heitman and Professor Gerard van Westen. She uses artificial intelligence and structure-based approaches to characterize the role of GPCRs in cancer.
“My PhD research is quite broad” says Gorostiola Gonzalez. “Some of my projects are very zoomed-out. For instance, we have just published a systematic inventory of mutations that we found in GPCRs in publicly available cancer databases. We analysed what patterns we could see, and what kind of information we could deduce from that. This knowledge can be used to develop cellular essays, such as the ones that Natalia is working on. I also have projects in which I study the three-dimensional structure of GPCRs, trying to determine how they interact with different compounds. For instance, I could try to identify pockets that could fit allosteric modulators. In other projects, I use structural approaches to explore ways to specifically target GPCRs with an abnormal structure. If we could design compounds that specifically target these abnormal receptors, these compounds would be selective and thus safer for patients.”
Impact for cancer patients
The chemical compounds that the Heitman Lab is studying may be developed into novel anticancer drugs, or into a co-therapy that makes existing drugs more effective. This makes the lab a valuable addition to the Oncode community. “Our research takes place at the beginning of the drug discovery pipeline, investigating novel concepts, targets and compounds. The majority of Oncode Investigators work further along the pipeline, with preclinical and clinical models. When I joined Oncode in 2019, I found it both exciting and overwhelming. There were so many things that I did not know about the field of oncology, and I hardly knew any other Oncode Investigators. I quickly decided that the only way to make this work was to create a slide deck and ask people if they would be willing to have us talk about GPCRs and cancer. Natalia and I visited a lot of labs to make people aware of the importance of GPCRs and we started valuable collaborations. What we add to the Oncode community is expertise at the level of drug targets and the interaction of various compounds with these targets. We explore how this interaction can be modulated to gain efficacy and safety, tailored to the mechanism of action that is needed in a particular situation. This may ultimately result in a pharmacological toolbox to treat cancer patients more effectively and safely”, concludes Heitman.
Credits: interview by Linda van den Berg; photography by Marloes Verweij, Laloes Fotografie