Multi-tasking drug combats cancer

ArticleQ&ADetailDownload pdf
Professsor Hong-yu Li, of the University of Arkansas for Medical Sciences (UAMS), has dedicated himself to the discovery and development of new drugs, particularly for the treatment of cancer. His pioneering approach uses computer modelling and a novel screening technique to develop drugs that can target multiple facets of tumour growth, minimising the development of drug resistance. His latest discovery, ‘Pz-1,’ shows great potential for treating advanced medullary thyroid cancers.
Cancer is one of the world’s leading causes of premature death, and one of the most feared. Although cancer treatments are rapidly becoming more sophisticated and able to target tumour cells or their environment very precisely, most drug therapies remain ‘single target’ therapies. That is, they attack one key pathway of cancer growth or survival, such as its blood supply. Single target therapies are at high risk of drug resistance, as tumour cells can mutate – presenting a ‘moving target’ that drug discovery may be unable to keep up with. Many current therapies also produce unwelcome side effects, significantly reducing cancer patients’ quality of life.
Polypharmacology to the rescue
One way to get around the resistance problem is by designing and optimising drugs for the balanced activities on multiple pathways required for tumour growth. Prof Li calls this ‘Synergistic Medicinal Chemistry.’ A leading practitioner of the discipline known as ‘targeted therapy,’ Prof Li considers that the traditional ‘one drug, one target’ approach is inadequate. Instead, he says, the future of modern medicine lies in single agents with multiple molecular targets, providing the benefits of combination therapy within a single molecule, and thereby limiting any risk of drug-drug interactions.

The future lies in single agents with multiple molecular targets, providing the benefits of combination therapy within a single moleculeQuote_brain

Prof Li’s research team at University of Arkansas for Medical Sciences (UAMS) uses an iterative combination of computer modelling to design potential clinically-relevant molecules, with a clever technique of ‘fragment-based chemical screening’ using a library of potentially useful small molecules which have been chemically modified to make them larger and easier to screen. At present the research is focused on one particularly powerful molecule, Pz-1. Pz-1 was developed through multiple iterations of the modelling-screening procedure, generating a new molecule with greater potency than its predecessors.

Balancing activities for the synergistic effect
Balancing activities for the synergistic effect in vivo.
Pz-1, like many of the compounds Prof Li has discovered, is a kinase inhibitor. This means it blocks the action of enzymes called kinases, which are commonly found in cellular signalling pathways controlling growth and development. Many kinase inhibitors are already in use as anticancer drugs, for instance in the treatment of leukaemia. Each kinase inhibitor is designed to target one kinase, and thus to inhibit one pathway. Pz-1, however, has two different parts which enable it to block two separate kinases, both involved in different, crucial, cancer pathways.
Tackling thyroid cancer
Prof Li’s lab uses Pz-1 to target a rare cancer of the medullary thyroid. The thyroid is a small gland in the neck which secretes hormones controlling metabolism. Around 9,000 people are diagnosed with medullary thyroid cancer each year. The standard treatment for other thyroid cancers, radioactive iodine, is ineffective against medullary thyroid cancer. Other current treatment options tend to provide only partial or temporary inhibition of tumour growth, whilst also being prone to adverse side effects.
One of the key features of medullary thyroid cancer is that it is often heritable, and associated with changes in a cancer-causing gene (an ‘oncogene’) known as RET, which codes for a kinase called RET. Existing treatments for medullary thyroid cancer (vandetanib and cabozantinib) are also kinase inhibitors and are effective against some forms of RET, but not against several of its drug-resistant forms including one known as the ‘gatekeeper’ mutation.
Pz-1 binds and blocks the action of RET, including, crucially, resistant forms like the gatekeeper mutation. It also binds and blocks the action of another protein, VEGFR2. VEGFR2 stands for ‘vascular endothelial growth factor receptor 2’ and, as its name suggests, controls the growth of blood vessels supplying tumours induced by RET. Pz-1 has balanced actions on all three enzymes: RET, VEGFR2 and RET gamekeeper mutant. Thus, Pz-1 can slow a tumour’s growth both by blocking RET-based signalling pathways, by cutting off its blood supply and, in turn, its source of oxygen and nutrients.

Pz-1 can slow a tumour’s growth both by blocking RET-based signalling pathways, and by cutting off its blood supplyQuote_brain

Prof Li’s studies in mice indicate that Pz-1 is effective equally against RET, RET gatekeeper mutant, and VEGFR2 at concentrations as low as 1 milligram per kilo of bodyweight, and that at such low doses it causes no detectable side effects. In fact, toxic effects were not even observed at doses 100 times greater than this. One reason for the lack of toxic effects is its specificity: screens show that Pz-1 interferes with the action of very few of the body’s useful kinase enzymes in non-cancerous tissue. However, the large safety window could largely be a result of the synergistic inhibition of RET, RET gatekeeper mutant, and VEGFR2. As Prof Li puts it, the discovery of Pz-1 ‘validates the effectiveness of the synergistic medicinal chemistry approach,’ producing safer, more tolerable medications and a better quality of life for cancer patients.
A more selective approach
In some patients, however, the dual activity of Pz-1 against RET and VEGFR2 may pose problems: while the RET inhibition is effective at limiting cancer growth, the action on VEGFR2 can cause adverse effects such as high blood pressure elsewhere in the body. Thus, Prof Li’s most recent research, funded by the US National Institutes of Health, is aimed at developing a derivative of Pz-1 that maintains RET activity only as a back-up strategy for Pz-1.
Medullary thyroid cancer may be rare, but its importance lies in its role as a model system for other forms of cancer. The RET gene is now known to drive the development of tumours in other parts of the thyroid, the adrenal glands, rare cancers of the lung and colon, types of leukaemia, and a multi-tumorous condition known as MEN2B syndrome. The establishment of a polypharmacology protocol to combat these RET-related cancers represents, Prof Li believes, a paradigm shift in our approach to drug development for the targeted treatment of tumours of many types.

How did scientists first discover the importance of kinase inhibitors in cancer treatment?
In the early 1990s, kinase research became a new paradigm for the drug discovery and development of cancer therapeutics in academic research organisations. At the time, many industrial scientists were sceptical about whether the selectivity of kinase inhibitors could be achievable. Gleevc (Imatinib) was the first kinase inhibitor approved into the market in 2001. Dr Brian Druker from Oregon Health & Science University and Dr Charles Sawyer from the University of California Los Angeles (now with Sloan-Kettering Cancer Centre) contributed to its development significantly. Gleveec, which is a very selective kinase inhibitor, revolutionised the treatment of chronic myeloid leukeamia.
Why did you decide to focus your research on such a rare cancer, medullary thyroid cancer?
After working with Eli Lilly and company for nine years, I joined the University of Arizona as an associate professor. At Eli Lilly and company, more than 100 million dollars were budgeted for delivering an investigational new drug (IND) into the phase I clinical trials. In the academic world if we are awarded 10 million to do the same, we are lucky. Therefore, it would be better to avoid a direct competition with industry. Medullary thyroid cancer is a rare cancer and Ret was a neglected target in the drug discovery value chain.
Pz-1 is important for its ‘polypharmacological’ effect – yet your current NIH study aims to reduce one of its effects (on VEGFR2) in order to promote the other (on RET). How will this avoid bringing back issues of drug resistance?
The R01 funding mechanism goes through an expert evaluation process and favours low risk projects. The novel concept may not be received well in the review process. By using the novel concept ‘Synergistic Medical Chemistry’, the start-up funding from the University of Arizona helped us to discover and develop Pz-1. We were then awarded with an NIH R01 to develop a selective inhibitor as the back-up drug candidate.
What impact do you hope your research will have on the treatment of cancers in general?
Synergistic Medicinal Chemistry could become a main research area to discover and develop novel targeted agents, especially for the cancer treatment in next 10 or 20 years. Although several very selective kinase inhibitors such as Gleevec were very successful, especially for liquid cancers, the superior selective inhibitors are generally not working well due to rapid drug resistance. The synergistic inhibition/or activation of two or more targets could overcome or mitigate the drug resistance. The approach could also transfer non-durable targets to drugable. Therefore, synergistic medicinal chemistry could expand the drugable target landscape.
What next steps need to be taken to bring Pz-1 and its derivatives into clinical use?
We are in the process of the IND studies and expect that the drug could enter the clinical trial this year. Although we are continuing to develop a selective RET inhibitor as a back-up drug candidate, we still believe that Pz-1 would do much better than a selective RET inhibitor in patients. The selective RET inhibitor could serve as a chemical probe to validate the RET biology in other cancers.
Research Objectives
Professor Li’s research is focussed on drug discovery and development, with a particular focus on oncology. His team have pioneered a novel drug discovery approach. This new direction of Synergistic Medicinal Chemistry, optimises the potency of drug targets. His group also employ a sophisticated computer modelling fragment-based chemical screening to hunt for potentially potential therapeutic molecules.
Funding

  • National institutes of Health (NIH)

Collaborators

  • Professsor Hong-yu LiBrendan Frett, Ph.D Assistant Professor, UAMS
  • Massimo Santoro, MD, Ph.D. Professor of General Pathology, Francesca Carlomagno, MD, Ph.D, Associate Professor, Università di Napoli Federico II, Italy

Bio
Professor Hong-Yu Li completed his PhD from The University of Tokyo and postdoctoral training at Columbia University and Harvard University. He led a team at Eli Lilly & Company who successfully discovered three small molecule kinase inhibitors that were tested in clinical trials, two are currently in phase II stage. He also significantly contributed the marketed CDK4/6 inhibitor, Verzenio (Abemaciclib) (FDA approval 09/28/2017). Prof Li is currently Arkansas Research Alliance Scholar and Professor at University of Arkansas for Medical Sciences (UMAS). He has co-founded two start-up companies.
Contact
Professor Hong-Yu Li
University of Arkansas for Medical Sciences
4301 W. Markham St., Little Rock, AR 72205, USA
E: HLi2@uams.edu
T: +1 501 296 1154
W: https://pharmcollege.uams.edu/aboutus/contact-us/directory/faculty-member-hong-yu-li/

Related posts.

Comments.

Leave a Comment

Your email address will not be published. Required fields are marked *

Share this article.

Share on facebook
Share on twitter
Share on whatsapp
Share on linkedin
Share on reddit
Share on email