Remodeling of Cell Surfaceomes in Cancer

Kent Simmons:
Welcome, everyone, to this Cambridge Healthtech Institute podcast, which we're presenting in conjunction with the 17th annual Peptalk event, which will be held January 8th through the 12th of 2018 at the Hilton Bay front Hotel in San Diego.

I'm Kent Simmons. I'm a program director with CHI and with me today is Dr. James Wells, professor of pharmaceutical chemistry at the University of California, San Francisco, and the presenter of the opening keynote presentation in the Emerging Technologies for Antibody Discovery meeting to be held on January 11th and 12th at Peptalk.
Thanks very much for joining us today, Jim.

Jim Wells:
Well, Kent, thank you very much for inviting me. I'm honored to be a speaker there and delighted to talk about our current work at the Peptalk symposium.

Kent Simmons
Your lab focuses broadly on how cell surfaces change in health and disease, and I wondered if you can start in our discussion today with some background on this work and how these understandings impact the discovery and development new bio-therapeutics.

Jim Wells:
Sure. This is actually inspired by an experience that I had at Genentechs many years ago when I was witness to the development of the HER-2 antibody, inspired from studies from Dennis Slamon's lab at UCLA that HER-2 is over-expressed on a good portion of breast cancer cells. That being so, Genentech embarked on developing therapeutic antibody to that upregulated antigen and, ultimately, into three different drugs to that antigen.

We wondered, "Well, there should be many more of these kinds of opportunities," and there have been. Biotech, I think, has about 20 different tumor-specific antigens that they've been focused on, but there's about 4,000 different membrane proteins. Could there be others beyond that small subset that's currently the focus of many Biotech investigations?

Kent Simmons:
At Peptalk, your keynote is gonna discuss new findings relating to the role of the cell surface proteome, or as you term it, the surfaceome, in the metastasis of cancer. Can you tell us a little more about the surfaceome and how this functions in cancer growth?

Jim Wells:
Yeah. There's a really nice review, a classic review, by Weinberg and Hanahan which describes what cancer cells need to achieve in order to surface. This is a now updated review in 2011 in the cell paper. They needed to achieve a number of things, including activating invasion and metastasis, inducing angiogenesis, deregulating cellular energetics, sustaining proliferative signaling, and the list goes on.

There's about ten different challenges that cancer cells have, and so when we do our surface cell map, what is upregulated. For instance, in a KRAS transformed cell we find that many of the proteins we find can be mapped to these functions. Actually, when KRAS transforms a cell, it doesn't just induce one upregulated antigen. Rather, it induces a whole team of upregulated antigens and so it changes our perspective about how to think about modulating this team of proteins.

Kent Simmons:
Then where do you go from here in translating the work of your lab into the development of new therapeutic antibodies or other bio-therapeutics?

Jim Wells:
Yeah, that's a great question and one that we're only starting to chip away at because a lot's involved in validating targets for drug discovery, but in nutshell, I think we're interested in which of the proteins that become upregulated as well as which in those upregulated proteins could become targets from immuno-therapy, antibody based therapy, recruiting the immune system to those cells, targeting those cells to kill them selectively.

Obviously, selectivity is a key issue, and one that needs to be looked at very thoroughly so that one is targeting things on the tumor and not in the normal tissues. That's a very involved process of trying to distinguish which would be good targets versus bad versus

We've been interested in looking at happens if we knock down these targets on the surface and find out which are synthetically lethal with KRAS transformation. The combination of those two can then direct us to interesting targets, and because we see teams of proteins come out, we wonder if we can get better selectivity by building by specifics and this is a classic criteria that Biotech companies are using now. To ask that question, are there ... Can you get better selectivity by bring in two different upregulated antigens.

Kent Simmons:
In the audience, for your talk at Peptalk, you'll have a lot of people working from industry labs that are focusing on cancer immunotherapy and immunotherapy combinations and so forth. What are the implications of some of your work on the more broadly focused work going on across the industry in the develop of new cancer treatments?

Jim Wells:
We would hope that we bring more tumor-specific antigens to play, perhaps even complexes of them, and that those then can add to the armamentarium of options one has when targeting tumors. We're a long ways from having validated antigens that we would shout and scream that people should be targeting for cancer immunotherapy, but I think we have a number of promising leads, and we hope to inspire others to follow up on these.

Kent Simmons:
What are some of your near term goals for this research, maybe over the next year? Where do you see this going during that period of time?

Jim Wells:
There's several irons in the fire. One is to expand what we're doing to a number of other oncogenes to see what are in common with the kinds of oncogenes that are big players in cancer. Two, expand the surfaceome technology. I'll be describing a new technology that we've developed called phage antibody next-generation sequencing where we can use antibody probes on phage to multiplex and use them to pan screen many different cell lines to find out how receptors are changing on the surface of the cell. It's a companion to proteomics, but a completely orthogonal method and has, I think, great potential because we can multiplex man, many targets at once.

Kent Simmons:
Well, it's certainly a very exciting time for technology these days, and I think it's interesting to hear about the way that you're combining some of these tools in your group to advance this field of science. I wanted to thank you for your time today, Jim, and we certainly appreciate you joining us for this podcast recording and I'll look forward to seeing you in January and hearing you talk at the Peptalk conference.

Jim Wells:
Okay, thanks a lot. I'll look forward to being there and meeting others.

Kent Simmons:
Thank you everyone for listening today. This has been an interview with Dr. Jim Wells, a professor of pharmaceutical chemistry at the University of California, San Francisco and the presenter of the opening keynote presentation in the Emerging Technologies for Antibody Discovery meeting to be held on January 11th and 12th at Peptalk.
If you'd like to register for Peptalk or learn more about the more than 300 scientific presentations at the event, please visit www.chi-peptalk.com. This has been another Cambridge Healthtech Institute podcast. I'm Kent Simmons and thank you for listening.