Mario Suva and Ramesh Shivdasani are tackling some of the toughest, meanest cancers to clear a path to better treatments.
- Suva and Shivdasani are using every approach in their arsenal to figure out what makes cancer cells arise from healthy tissue.
- Armed with enough new knowledge about how cancer arises, they want to take truer aim at cancer cells, the cancer cell lineage, and factors that make cells go awry.
- Their new approach to cancer management would combine gene and cell therapies to kill the cancer without damaging healthy cells.
In the HSCI Cancer Program, Mario Suva and Ramesh Shivdasani are trying to figure out why cancer cells make such bad choices for their hosts. Their goal is to combine cell and gene therapies into a perfect weapon to assassinate cancer cells without harming healthy tissue.
Chemotherapy and radiotherapy are scorched-earth tactics in the battle with cancer, and leave a lot of collateral damage in their wake. The HSCI Cancer Program is reimagining cancer treatment, seeking to combine cell therapies like immunotherapy with gene editing to destroy both cancer cells and their entire lineage.
Building such precise weaponry demands a deeper understanding of how stem cells choose their fate. Now, technologies have caught up to make such insights possible.
Killing stem cells
“Most of the HSCI is concerned with getting stem cells to regenerate tissue, and that sets us apart. We’re the one HSCI disease program that wants to kill stem cells,” says Shivdasani. “But until we have a much deeper understanding of how all of the different cellular networks connect to one another, we will not be able to make the kind of progress that the field needs.”
Shivdasani’s lab is based at the Dana-Farber Cancer Institute. He investigates intestinal cells to figure out why some stem cells go rogue and turn into cancer. Shivdasani works closely with Suva, whose lab at Massachusetts General Hospital investigates brain cancers.
“I study brain tumors – gliomas, which affect both adults and children,” explains Suva. “It is an exceedingly vexing problem, because I’ve witnessed the field of oncology going through waves of progress. The prognosis for melanoma, of lung cancer, and a whole set of other malignancies has changed. But not one of those waves has had major impact on gliomas.”
“I think we need to reimagine drugs for brain cancer. In five years’ time, I would like to have something to treat people with that is completely different from what’s on the market now,” says Suva.
“We need to know exactly what we are dealing with, first and foremost,” he continues. “To do that, my group uses many different approaches. One is single-cell genomic technologies, which let us characterize individual cells in a tissue, rather than lumping groups of cells together. That way, we can see things much more clearly.”
For Suva, efforts like the Human Cell Atlas and Tumor Cell Atlas are opening up new possibilities for research by offering a high-resolution look at all the characteristics of normal and tumor cells. The group is flagging the unique features of malignant cells to bring them out of hiding.
“I’m optimistic about our approach. We’re refining the tools that allow us to characterize the cells that drive brain cancer and their genetic programs," says Suva. “At the same time, the field of immuno-oncology is also making tremendous progress to re-engineer immune cells.
“So we have the tools to understand brain cancer better, and to target specific cell types more effectively. Both those developments are very new, and the combination makes our work all the more interesting.”
But new technologies only take you so far. For both Suva and Shivdasani, cancer research demands a truly multidisciplinary approach.
“I work with intestinal stem cells, where we know all too well that the native, normal stem cell is also the cell of origin for colon cancer,” explains Shivdasani.
“If you get rid of stem cells in the intestine, it doesn’t make a difference – the tissue simply makes new stem cells out of whatever cell types are on hand. If you kill the cancer stem cells, the tumor should evaporate – but it doesn’t. Differentiated cells revert to the stem cell compartment. You can keep killing them, but more cells just keep coming back.”
According to Shivdasani, these findings could only have been found through very careful experimental investigation in the ‘wet’ lab.
“No fleet of sequencing machines or armies of statisticians would ever have been able to solve or understand this,” he says.
Taking out the family tree - but which one?
Starting from the time that they’re very small, cancers metastasize, and that is very strange.
“That is a highly irregular behaviour,” reflects Shivdasani. “These cells overcome some severe barriers that prevent our normal kidney, liver, and blood cells from going to the wrong places and growing. Maybe all of our cells travel all the time, but if a liver cell finds itself in the heart, it’ll probably last less than 10 minutes and die because the environment is hostile. But cancer cells? They can circumvent those kinds of barriers, and we need to understand how they do that.”
Cancer is driven by genetic events. One approach to drug development is to design a small molecule that will block the genes or proteins involved.
But cancer is also driven by highly specific cell types, in a particular state. Another approach would be to block that cell type and its entire family tree, including all the branches.
“But we don’t know enough about these cell types, their lineage, or their allies for all malignancies. We simply need more comprehensive, high-quality information about cell types and their genetic programs if we are going to take better aim at our target,” says Suva.
“Once we have that information, we’ll need to design ways to target the cell’s lineage without harming its normal stem cell counterpart.”
What it will take
“What these problems demand, and the kind of solution that HSCI is ideally positioned to achieve, is to combine high-throughput data gathering with careful reasoning grounded in the principles of developmental biology and cell differentiation,” offers Shivdasani. “Then we can find our targets, and take them out.
“I don’t have any doubt in my mind that this will come to pass. And I think that the road, like anything else in science, will be a winding, topsy-turvy kind of road. It requires the kind of deep data gathering, but also very thoughtful experimentation.”
“We have learned quite a lot about gliomas and the driving force behind them, but it’s just a start,” adds Suva. “From there on, it’s a long road to changing the management of these tumors. But I am encouraged that we do have a clear path forward, and can take steps in the right direction.”