Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And joining me today is Dr. Daniela Matei. She's the Chief of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology at Northwestern Medicine, and she's the Diana Princess of Wales Professor of Cancer Research at the Lurie Cancer Center.

Today, we're discussing a groundbreaking study on chemotherapy-resistant ovarian cancer with Dr. Matei, who has made significant strides in understanding the disease's relationship with cholesterol. Dr. Matei, thank you so much for joining us today. This is fascinating. Your findings built on earlier preclinical research from Thaxton and Leo Gordon, MD, using nanoparticles to treat lymphoma. Can you explain a little bit about the significance of discovering that this approach will also work in chemotherapy-resistant ovarian cancer cells and their increased uptake of cholesterol?

Daniela Matei, MD: Thank you, Melanie, for having me on this podcast. My laboratory has worked for several years on trying to understand the pathways that platinum-resistant ovarian cancer cells use to survive the toxic effects of chemotherapy. We've been particularly interested in this subject, because the majority of patients with ovarian cancer eventually developed platinum resistance and treatment for platinum-resistant ovarian cancer is generally limited. Only two drugs have been approved over the past two decades and the majority of chemotherapy drugs that have been tested for women with platinum-resistant ovarian cancer induce response rates in single digits. Therefore, the clinical significance of finding new therapeutic approaches for women with platinum-resistant ovarian cancer is very high.

The findings that you are referencing in regards to our paper recently published build upon previous observations coming from our laboratory that have shown that platinum-resistant ovarian cancer highly depend on the intake of lipids, of fat. We have published two years ago in Nature Communication the fact that platinum-resistant ovarian cancer cells and tumors from patients rely on high uptake of fatty acids to survive.

Following up on those studies, we also examined the role of cholesterol in platinum-resistant ovarian cancer cells and tumors. And not surprisingly, we found that these cells are loaded with cholesterol compared to the platinum-sensitive ovarian cancer cells and tumors. Having made this observation, we partnered with Dr. Shad Thaxton from Northwestern, who bioengineered novel nanoparticles that block the receptor for the HDL cholesterol and made the discovery that these nanoparticles, in fact, were quite effective in reducing tumor burden as well as inducing cancer cell-killing particularly in models that were resistant to traditional chemotherapy.

Melanie Cole, MS: Wow, that really is absolutely so interesting. So, expand a little bit for us how does the synthetic nanoparticle work to block cholesterol uptake in cancer cells and really what led to the development of this approach?

Daniela Matei, MD: So, what we found was that the cancer cells are rich in cholesterol, and we asked whether this cholesterol is synthesized inside the cancer cells or whether it's imported from the outside. We found that the receptor SRB1 is present at higher levels in resistant compared to sensitive cancer cells or tumors, and that the resistant cells rely on cholesterol import. In fact, the synthesis of new cholesterol is somewhat inhibited in these resistant cells, suggesting that the platinum-resistant cancer cells rely on bringing cholesterol from the outside. The nanoparticles are designed to bind to this HDL receptor present on the surface of cancer cells. The nanoparticles mimic HDL cholesterol, but in fact do not contain any cholesterol. So when the nanoparticle binds to the SRB receptor, it blocks it and makes it unavailable to bring in additional cholesterol. Therefore, cancer cells or tumors that are treated with these nanoparticles are unable to uptake HDL cholesterol from the tumor microenvironment, and therefore, these cells or tumors become starved of cholesterol and they undergo cell death.

Melanie Cole, MS: Dr. Matei, can you elaborate on how reducing cholesterol triggers a cell death pathway in these cancer cells? Specifically, you've been mentioning HDL, where does LDL cholesterol fit in? And are statins a part of this study?

Daniela Matei, MD: All these are very good questions. Interestingly, the form of cancer cell death that is induced by the HDL nanoparticles is not the regular cancer cell death, which we refer to as apoptosis, but a rather a novel form of cell death referred to as ferroptosis. This ferroptosis is a form of cell death that depends on the presence of iron. And It is regulated by the presence of antioxidant proteins in the cancer cells. We had made the observation that platinum-resistant ovarian cancer cells and tumors are enriched in antioxidant defense mechanisms, and one of the proteins that plays a significant role in these cells is called glutathione peroxidase 4, in short, GPX4.

To summarize, we had previously found in a different study that the platinum-resistant tumors have high levels of GPX4, and this high level of GPX4 prevents ferroptosis. It's a defense mechanism against ferroptosis. What happens when we treat these platinum-resistant cancer cells with the HDL nanoparticle is that the antioxidant defense mechanisms are completely blocked, and the GPX4 protein is significantly reduced. And this leads to cancer cells death through feroptosis. We still don't know how this happens, and we suspect that cholesterol is an important buffer that maintains the redox homeostasis of cancer cells. It works like a buffer to prevent oxidative stress in the cells. So when cholesterol levels drop, cancer cells become more sensitive to oxidative stress.

You've asked about LDL cholesterol as well as about statins. We did examine indeed did what happens with the other pathway, which is the cholesterol synthesis pathway. And we found that the cholesterol synthesis pathway was in fact inhibited in the platinum-resistant cells. And that treating these cells with statins or with a combination of HDL nanoparticles and statins did not trigger additional cancer cell killing. So, we believe that what is important is the blockade of the cholesterol import into the cells and particularly of the HDL cholesterol import.

Melanie Cole, MS: Thank you for clarifying that. And the study mentions a reduction in ovarian tumor growth by more than 50% in human cells and animal models. Can you share more about these findings and their implications?

Daniela Matei, MD: indeed, our studies showed that in vivo treatment with the HDL nanoparticles inhibited tumor growth in murine models and also importantly in patient-derived xenograft models. These are tumors that are derived from humans and are implanted in mice and they resemble the growth of ovarian cancer in women. We were happy with our findings, but are also interested in improving upon the efficiency of HDL nanoparticles and are therefore interested in exploring the potential synergy between the HDL nanoparticles and chemotherapy such as carboplatin or paclitaxel. And furthermore, we also are interested in exploring the potential synergy between HDL nanoparticles and immunotherapy, and these are studies that we're planning for the future.

Melanie Cole, MS: If it's used in clinical practice, Dr. Matei, how would this approach compare to alternative treatments? And I'd like you to take us from bench to bedside and combine all these for us.

Daniela Matei, MD: As I mentioned earlier, treatments for platinum-resistant ovarian cancer have generally induced modest response rates in the, you know, 5-10% range. And therefore, there is a clear need to bring novel therapy such as this from bench to bedside. Of course, there is still a long line of research required before being able to bring this therapy to patients, including toxicology studies, as well as potential refinement of the therapy in terms of dosing and combination with either other chemotherapy or biological treatments. We hope to be able to achieve this. Of course, funding is required for additional studies, and I'm happy to continue to work on this with Dr. Thaxton and his colleagues.

Melanie Cole, MS: This is such an exciting study, Dr. Matei, and such an exciting time in your field. So, what are your next steps in your research, particularly regarding the combination of these nanoparticles with traditional chemotherapy and the effects of the nanoparticles on immune cells that fight against cancer? What's next for you?

Daniela Matei, MD: Well, we just submitted a grant to the Department of Defense and we have to trust that it will be funded so that we can continue our work. But this is exactly what we plan to do. We have seen a good synergy between the HDL nanoparticles and carboplatin and between HDL nanoparticles and paclitaxel in vitro. We have to test these combinations in murine models again. We are also interested to explore the effects of HDL nanoparticles in combination with immunotherapy. And this is of particular interest, because the growth of tumors is dependent not only on the cancer cell proliferative ability, but also on the immune cells present in the tumor microenvironment.

And interestingly, several types of immune cells present in the peritoneal microenvironment also depend on the presence of cholesterol. We, therefore, rationed that depleting this cholesterol from the tumor microenvironment might be able to reduce the presence of certain immune cells that play a suppressive role, particularly myeloid-derived suppressor cells. And by reducing these cells, the presence of these cells in the tumor microenvironment, this could have an additive anti-tumor effect and induce a better response. Therefore, we are interested in combining the HDL nanoparticles with immunotherapy. This is very novel. And as you know, immunotherapy has induced only modest efficacy in ovarian cancer; however, finding novel combinations of immune check inhibitors with new biologic drugs such as HDL nanoparticles could potentially improve efficacy.

Melanie Cole, MS: Thank you so much, Dr. Matei, for joining us and sharing the exciting implications of your study. Thank you again. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org to get connected with one of our providers. That concludes this episode of BetterEdge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.