Chapter 05: Developing Tools to Monitor and Screen for Ovarian Cancer

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Chapter 05: Developing Tools to Monitor and Screen for Ovarian Cancer

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Description

In this chapter, Dr. Bast notes the tools being developed for to screen for and monitor ovarian cancer. He begins by describing a study of auto-antibodies. Next he describes the SQUID detector (superconducting quantum interference device) that his laboratory is studying to fine-tune detection of presence of ovarian cancer cells. Funding comes from a SPORE grant. The project is part of the Moon Shots program.

Identifier

BastRC_01_20140707_C05

Publication Date

7-7-2014

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Discovery and Success; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; On Research and Researchers; Overview; Definitions, Explanations, Translations; Discovery and Success; MD Anderson Impact

Transcript

Tacey A. Rosolowski, PhD:

Okay, I just had the recorder off briefly, as Dr. Bast took a phone call. But we are back recording at twenty minutes after ten. So, what’s the next part of—we’re into your research story, here, which is exciting. So—(laughter)

Robert Bast, MD:

Soon after the CA125 assay was developed, we had the opportunity to test serum from a patient, who had a completely different illness, acquired hypo-gammaglobulinemia.

Tacey A. Rosolowski, PhD:

Could you repeat that one, please?

Robert Bast, MD:

Yeah. Acquired, A-C-Q-U-I-R-E-D, hypo, H-Y-P-O, gamma, G A M M A, globulin, G-L-O-B-U-L-I-N, emia, E-M-I-A.

Tacey A. Rosolowski, PhD:

Emia, oh, globulinemia. Okay. Got you.

Robert Bast, MD:

Yes, a disease that was treated with immunoglobulin injections, so that her physicians had been saving her serum to measure immunoglobulin levels. While being treated, the patients had developed ovarian cancer. So, it was possible to go back and determine whether her levels of CA125 had been elevated prior to the time that the cancer was diagnosed clinically.

Tacey A. Rosolowski, PhD:

Mm-hmm?

Robert Bast, MD:

And when we broke the code, we found that the CA125 started to go up linearly on a log scale for about ten to twelve months prior to the development of the clinical disease. After cytoreductive surgery, CA125 went down, and when she had chemotherapy, it went down even further. But it really looked like that there was lead time. So, working with Steve Skates [PhD] and Nina Einhorn [MD] in Stockholm, and ultimately then with Ian Jacobs [MD] in London, it’s been possible to see whether CA125 would be useful for early detection of ovarian cancer. Steve had developed an algorithm that would plot the course of CA125 over time, and to see whether any rise was something you’d worry about a lot or worry about a little, and where you could set each patient’s individual baseline. With that “ROCA” algorithm it was possible to identify patients with ovarian cancer even within the normal range of CA125. If CA125 levels went up, an ultrasound was performed. If the ultrasound was abnormal, surgery was performed. So, there have been several studies of that over the years in Stockholm and in London, and for the last thirteen or fourteen years, there have been two studies going in parallel, a very large study in the UK of 200,000 women—

Tacey A. Rosolowski, PhD:

Wow.

Robert Bast, MD:

—which the results should be back late this year or early next. And that’s large enough to determine whether there’s really a survival or mortality advantage to screening, which will be very important. With Karen Lu here at MD Anderson, we’ve been working with a much smaller study including 5,000 women, here in Houston, and in Dallas, Des Moines, Iowa, Providence, Rhode Island and Morristown, New Jersey. With this smaller group, we can still determine the specificity of the screening strategy and how many operations will be required to detect each case of ovarian cancer. One of the challenges with ovarian cancer is that it is neither common, nor rare. The prevalence in women who are over fifty and are at greatest risk of developing ovarian cancer is about one in 2,500. So, you’ve got to have high sensitivity to detect the early stage of disease, but you’ve got to have very high specificity, like, 99.7 percent, just to have ten operations for each case of ovarian cancer detected. Both in the UK study and in the NROSS study that we’ve coordinated here at Anderson, we only did three to four operations for each case of ovarian cancer detected.

Tacey A. Rosolowski, PhD:

Really?

Robert Bast, MD:

So, the specificity of putting together the algorithm with ultrasound is quite high, and it would be practical. So, if the UK study actually shows that there is a survival advantage, or better yet, a mortality reduction, we’ve shown that that’s practical here in the United States, and get exactly the same answer in terms of specificity. A lot of our research has been dedicated to trying to improve on CA125, and we found three other blood tests, or at least two other blood tests for sure, that give you a slight improvement over CA125. But it would need a much more sensitive early detection system, so we’re focusing a lot of our efforts these days on autoantibodies that can develop—a patient can develop antibodies against her own ovarian cancer. Antibodies against the p53 protein show up a year or more before detection of the disease. This only detects 20-25% of patients, so we need additional autoantibodies. We currently have been looking for autoantibodies against ovarian cancer with a chip that has 17,000 human proteins produced by Origene, and—

Tacey A. Rosolowski, PhD:

Produced by?

Robert Bast, MD:

It’s a company Origene, O-R-I-G-E-N-E. And what’s special about the chip is that these are human proteins expressed in human cells, so you get the right folding and the right glycosylation, and that consequently, the right epitopes for autoantibodies. And with that, we got more than a couple hundred candidates that would show up a year before the detection of disease by CA-125, so we’re currently trying to improve on that. The other thing that’s encouraging these days in terms of early detection is that I’ve been working with a company, a small startup company in New Mexico that has a SQUID detector. This is a superconductive quantum interference detection. And that’s a very sensitive way to measure magnetic fields. It’s so sensitive, you can actually measure the magnetic fields around synapses in the brain.

Tacey A. Rosolowski, PhD:

Wow.

Robert Bast, MD:

But if you have magnetic ferritin nanoparticles detached to antibodies that react specifically with ovarian cancers, you can detect perhaps as few as 105 ovarian cancer cells.

Tacey A. Rosolowski, PhD:

So, how does it work? Do you have to attach a nanoparticle to the cancer, and then you see—

Robert Bast, MD:

No, this would be attaching the nanoparticle to the antibody, then injecting the antibody either intravenous or intraperitoneally, having the antibodies stick to the cancer cells. And as long as the antibody’s in the circulation, you don’t get any signal. And as soon as it lines up on the surface of the cancer cell, you reinforce the effect. And so, you get a delay in relaxation of a magnetic pulse measured by Superconducting Quantum Interference Detection (SQUID). With John Hazle here at Anderson, we have a SQUID machine on south campus, and we’re trying to see if that fact is going to be as good as it’s supposed to be, in terms of detecting that in the cells. The current screening trials in the UK and at MD Anderson use rising CA-125, followed by ultrasound. A significant limitation of this approach is that ultrasound is not optimally sensitive, and as many as one third of ovarian cancers are now thought to arise, in the fallopian tube.

Robert Bast, MD:

The ultrasound really doesn’t detect those fallopian tube cancers. And it also is not able to see cancers much smaller than a millimeter or two. And with this SQUID technique, presentably, and it should be possible to see much smaller deposits of cancer either in the ovary or in the fallopian tube. But we need to find out if that, in fact, is the case. So, we’re trying to improve the first stage of early detection with other blood tests, or for other antigens, and also trying to improve the second step of that with something that’s much more sensitive than ultrasound, is the SQUID technology.

Tacey A. Rosolowski, PhD:

So, is this SQUID machine, is it like an MRI? The whole body goes into it? Or—

Robert Bast, MD:

Well, currently, it’s on a much less grand scale. It’s basically a detector with liquid helium that is over a platform. And currently it’s about mouse size for the prototype.

Tacey A. Rosolowski, PhD:

Oh, because it’s on mice right now?

Robert Bast, MD:

This is on mice.

Tacey A. Rosolowski, PhD:

Okay. I was getting overly excited and thinking we were at clinical trials.

Robert Bast, MD:

Well, there’s no reason why you couldn’t scale this up. And the nice thing is, it’s not exactly the imaging, it’s a detector. So, you could actually take this, even the machine we have now and focus—and if you had a patient with rising CA-125 or rising antibodies, and you couldn’t see anything on ultrasound or CT or MRI, you could imagine injecting the antibody with antibody-coated ferritin nanospheres, coming back several hours later, and just putting the probes over one or the other ovary, and to see if you’ve, in fact, got a delay in the relaxation of magnetic pulse.

Robert Bast, MD:

So, you wouldn’t really have to see a shape of an ovary, just to know whether the nanoparticles are localized there.

Robert Bast, MD:

And so, that, we’re currently evaluating that, as well. So, when we’re doing this, we’ve been doing this with the support of the NCI Specialized Program of Research Excellence (SPORE), but we’re also incorporating this in the moon shot. So, this is one of the areas where the moon shot’s been a tremendous element.

Tacey A. Rosolowski, PhD:

Maybe you mentioned this, but I kind of missed it in all the detail that was coming at me. What are the nanoparticles made of? And what is their special sensitive—how do they—why is it that particle, kind of particle, that’s being used to detect?

Robert Bast, MD:

Well, basically it’s iron containing particles that are coated with polyethylene glycol and antibodies. The iron can be magnetized. The SQUID measures quite precisely the time for relaxation of the magnetic particles to occur back to baseline.

Tacey A. Rosolowski, PhD:

Okay. Wow. Really, really interesting. So, I mean, given that this is part of the Moon Shot, that means that there is a hope that there would be a fairly short timeframe to get results from this. So, how do you see it transpiring? What are you looking for in terms of results?

Robert Bast, MD:

Well, certainly in terms of the, if the autoantibodies were affected, you would require probably in the next year, or at the most, two, to try to identify the optimal panel of autoantibodies, and to verify those with other databases.

Tacey A. Rosolowski, PhD:

And are you—

Robert Bast, MD:

And other serum banks.

Tacey A. Rosolowski, PhD:

And I’m just saying, are you—now, I just want to make sure I understand where the antibodies are coming in, because I may have missed that detail. So, is this—so, please explain that.

Robert Bast, MD:

The antibodies, of course, are present in serum, so that in addition to protein antigens being shed into serum, you can also find antibodies in serum. But it looks now as if those might be increased a whole year, before the CA-125 starts to elevate. We need to confirm that for sure. But if that, in fact, pans out with multiple serum samples from multiple serum bacs, you can image incorporating that in an algorithm that can then be used in the same population where we’ve been using CA-125, and the same 4,000 women, we could put that in to be sure that we’re not going to see too many false positives, so people are getting ultrasounds, or even worse, getting surgery that they didn’t need.

Tacey A. Rosolowski, PhD:

So, you kind of get a triple or quadruple process, where you’re looking for the proper antigen, the one that emerges as being, you know, very sensitive, and then C-25, unless that’s made obsolete by the antigen. Then—

Robert Bast, MD:

Yes, and probably, realistically, it’s going to be pick up the cases that CA 125 misses.

Tacey A. Rosolowski, PhD:

And then the next phase would be either ultrasound, and/or SQUID detection.

Robert Bast, MD:

Yes, exactly.

Tacey A. Rosolowski, PhD:

So, you’ve got kind of like four tools.

Robert Bast, MD:

And this SQUID probably is a three to five year project—

Tacey A. Rosolowski, PhD:

Okay.

Robert Bast, MD:

If it continues to be promising, we’ll know within the year whether this is as good as it promises to be, at least in terms of imaging, or in terms of detecting ovarian cancers in mice.

Tacey A. Rosolowski, PhD:

Interesting. Okay. So that’s, like, I mean, pretty amazing from when you first started working with ovarian cancer, where there was just nothing, to suddenly all of these tools.

Robert Bast, MD:

CA125 has also been used to detect disease recurrence. It has also been used as part of tests to identify women with pelvic masses, who need to be referred to a gynecologic oncologist for specialized surgery. And so, it’s been used in several different ways.

Tacey A. Rosolowski, PhD:

Interesting. Wow.

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Chapter 05: Developing Tools to Monitor and Screen for Ovarian Cancer

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