May 20, 2020

Study points to common protein duo as a new therapeutic target for several cancer types

Structure of the RUVBL1 protein. (Credit: Emw / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0))

Local research group discovers a new way to shut down a pair of cancer-driving proteins, pontin and reptin, using the structure of an FDA-approved drug

Pontin and reptin are proteins that are involved in several cancer-driving mechanisms and play key roles in several diseases, including liver, colorectal, breast, lung and bladder cancers. This makes them a hot target for cancer drug development and discovery efforts. Currently, there is only one drug class that may hold some promise to shut down these proteins, but a Toronto-based team of scientists has recently broken new ground.

Dr. Walid Houry’s Lab at the University of Toronto and OICR’s Drug Discovery group have discovered that pontin and reptin, also known as RUVBL1 and RUVBL2, may be blocked to prevent cancer growth using a chemical similar to the FDA-approved drug, sorafenib. Their findings, which were recently published in Biomolecules, could be a starting point for new and improved cancer drugs based on the approved drug’s structure and function.

Dr. Nardin Nano.

“Through our research, we detangled a large, complex process of interactions between proteins, but what we found was both rewarding and exciting,” says first author Dr. Nardin Nano, who was a PhD student in the Houry Lab while leading the study. “Our findings suggest a new target for cancer treatment and that a new therapy could be within reach.”

This study is part of a larger initiative, led by Nano and members of the Houry Lab, to further describe the function of these proteins in helping cancers grow and invade tissues. With their newfound understanding, the Houry Lab will continue to design and develop molecules similar to sorafenib that can better target pontin and reptin.

“I look forward to future studies that will use this knowledge to better inhibit these proteins in vivo,” says Nano. “Although there is more work to be done, I’m proud that this discovery can help guide future drug development efforts.”

“Given the multiple roles of pontin and reptin in carcinogenesis, it’s not surprising that they are promising drug targets,” says Houry, who is a Professor at the University of Toronto and supported by OICR’s Cancer Therapeutics Innovation Pipeline. “These findings motivate us to continue developing pontin and reptin inhibitors as potential anti-cancer compounds that could – one day – help a number of patients with the disease.”

May 13, 2020

Unexpected mitochondria activity in leukemia cells gives opening for new treatments

Mitochondria (yellow) found to be influencing gene expression within the nuclei (blue) of leukemia cells. (Credit: Torsten Wittmann, University of California, San Francisco)

Toronto researchers unravel key cancer-driving circuit between the “powerhouse” and the “brain” of leukemia cells, in big first step for future therapeutic discovery and development

Dr. Dilshad Khan.

Over the last few decades, research has suggested that mitochondria, also known as the “powerhouses of the cell”, play an important role in tumour growth and development, but little is known about how to prevent these cellular machines from wreaking havoc. In a recent study, scientists have discovered a key protein that is made in the “powerhouse of the cell”, unexpectedly affects the expression of genes in the nucleus, or the “brain”, of certain leukemia cells. The study was launched by Dr. Dilshad Khan, who – alongside colleagues in Dr. Aaron Schimmer’s lab at the Princess Margaret Cancer Centre – set out to determine which genes in the mitochondria were essential to the growth and viability of acute myeloid leukemia (AML).

Through genome-wide CRISPR screening and other gene-manipulating techniques, they discovered a key mitochondrial protein that AML cells can’t survive without – MTCH2. Their findings, which were recently published in Blood, may eventually lead to new ways to fight this common and fast-growing form of blood cancer.

“We found that the mitochondrial protein MTCH2 is essential for the growth and survival of AML cells,” says Khan, Postdoctoral Fellow in the Schimmer Lab, who is the first author of the study. “But finding this protein was just one piece of the puzzle. We needed to understand how it worked.”

With Khan’s expertise in epigenetics, the team systematically dissected how MTCH2 affects AML cells. They found that blocking this protein would ultimately cause leukemic stem cells – the difficult-to-treat renewable cells that are thought to be at the root of leukemia – to irreversibly transform into cells that are easier to eliminate with existing chemotherapies.

“Through a series of experiments, we unraveled how MTCH2 affects AML cells and discovered that this protein has a remarkable and unexpected impact on nuclear pathways – it could control nuclear gene expression to affect AML stemness and survival,” says Khan. “We never thought this could happen, but now that we’ve discovered these new links, we could potentially find new ways to control these mechanisms.”

Next, the Schimmer Lab and collaborators plan to investigate MTCH2’s specific mechanism to find where inhibitors – or potential cancer drugs – could block its path. These initiatives will add to Schimmer’s research on dysregulated mitochondrial pathways in leukemia, including his recent work on fat production and copper distribution in leukemic stem cells. This research is funded in part by OICR’s Acute Leukemia Translational Research Initiative and OICR’s Cancer Therapeutics Innovation Pipeline.

“This study showed us that mitochondrial proteins are more interconnected with other cellular networks than we thought,” says Khan. “These fundamental findings have shed light on new research avenues that we can pursue to find new solutions that will hopefully benefit patients with AML.”

April 8, 2020

Accelerating the development of new cancer drugs in Ontario

Drs. Lisa Porter and John Trant from the University of Windsor are working to develop a drug to block a protein that is elevated in some types of aggressive cancer. Disrupting the activity of this unique protein complex could slow or stop the disease. By providing researchers such as Porter and Trant with funding support and access to expertise, OICR’s Cancer Therapeutics Innovation Pipeline initiative is enabling the development of the next wave of made-in-Ontario cancer therapies.

July 24, 2019

OICR funding for Ontario drug discovery projects will accelerate development of new cancer therapies

The Ontario Institute for Cancer Research (OICR) has selected two new Late Accelerator projects to receive support through its Cancer Therapeutics Innovation Pipeline (CTIP) initiative. The projects, detailed below, will each receive up to $250,000 per year, for up to two years, to advance the development of drug candidate molecules. The projects were selected by an international expert review panel from 18 applications.

By joining the CTIP portfolio, these projects will receive more than just financial support – they will also benefit from the guidance of the Therapeutics Pipeline Advisory Committee, a group of industry and academic experts that provides advice on the scientific and strategic direction of CTIP projects.

“CTIP projects have great potential to improve treatment for patients, promote scientific collaboration and drive investment to Ontario’s biomedical research sector,” says Dr. Christine Williams, OICR’s Deputy Director and Head of Therapeutic Innovation. “These new projects are great examples of the innovative cancer therapeutics research happening in our province. We are excited to add them to CTIP’s portfolio of promising drug candidates and look forward to their progress.”

Funded projects

Identification of kinase inhibitors to block the tumour-promoting activity of YAP/TAZ for cancer therapeutics

Liliana Attisano, Principal Investigator, University of Toronto

Rima Al-awar, Principal Investigator, OICR

Frank Sicheri, Co-investigator, Lunenfeld-Tanenbaum Research Institute

Jeff Wrana, Co-investigator, Lunenfeld-Tanenbaum Research Institute

David Uehling, Co-investigator, OICR

Richard Marcellus, Co-investigator, OICR

Methvin Isaac, Co-investigator, OICR

The highly conserved Hippo pathway is a key regulator of cell and tissue growth. Virtually all solid tumours display pathway disruptions, which drive cancer initiation and progression. Mutations in pathway components are rare, making it unclear how to target the pathway for cancer treatment. This research group has shown that certain kinases are key regulators of the pathway that promotes tumorigenicity and observed that diverse human cancers display elevated levels of these kinases. Kinases are highly amenable to the development of targeted inhibitors; therefore, this project will identify potent and specific inhibitors with the long-term goal of establishing novel cancer therapeutics.

Development of kinase inhibitors for ovarian cancer: A novel first in-class immune-oncology therapeutic agent targeting tumor intrinsic stress states

Rob Rottapel, Principal Investigator, Princess Margaret Cancer
Centre

Tracy McGaha, Principal Investigator, Princess Margaret Cancer
Centre

Rima Al-awar, Principal Investigator, OICR

Methvin Isaac, Co-investigator, OICR

David Uehling, Co-investigator, OICR

Richard Marcellus, Co-investigator, OICR

Ahmed Aman, Co-investigator, OICR

The development of new cancer immune therapeutics has triggered a revolution with the recent advent of diverse strategies that engage the patient’s immune system. This research group has identified a novel kinase target that has the unique property of being both an emergent essential gene in high-grade serous ovarian cancer and a repressor of the innate and adaptive immune system. Additionally, they have demonstrated that target inhibition sensitizes cancer cells to cisplatin – a standard of care chemotherapy drug. This project will work to develop a “first-in-class” dual-action, anti-tumour and immune-oncology kinase inhibitors for ovarian cancer and potentially other cancer types.