Sanaz Memarzadeh, MD, PhD
Antibody-directed therapies have shown potential with investigational targets such as mesothelin and folate receptor alpha, but researchers are actively exploring approaches that target the prevalent p53
, explained Sanaz Memarzadeh, MD, PhD.
“If you look at the top 5 cancers that affect men and women, a large proportion of these patients carry mutations in p53,” said Memarzadeh. “p53
is the most commonly mutated gene in cancer. It’s seen in upward of 40% of tumors.”
In an interview at the 2018 OncLive®
State of the Science Summit™ on Ovarian Cancer, Memarzadeh, gynecologic oncologist and professor of obstetrics and gynecology, University of California, Los Angeles, detailed the early developments of antibody-directed therapies and restoring p53
function in the treatment of patients with ovarian cancer.
OncLive: What are some novel approaches that are being explored in ovarian cancer?
: Some of the research we are doing in our laboratory, in collaboration with investigators at UCLA, tie into one of these novel treatment options. The first approach is an immune-biologic approach with antibody-directed treatments. It utilizes the ability of an antibody to recognize an antigen expressed on a cancer cell. The antibody also carries a cytotoxic drug or a targeted drug that can be taken up by the cell. When the antibody binds to the antigen on the cell, it can go inside of the cell and directly target the cancer cell. What’s unique about this is the idea that it targets the cancer cell without targeting the normal cell. That is a major advantage of this approach.
The key to this approach is that you have to pick antigens that are highly expressed in the cancer cell but have low expression in normal cells. Antibody-directed targeted therapies against mesothelin is one approach. Mesothelin is a cell-surface protein that is expressed in ovarian and other cancers, including mesotheliomas.
The general concept is that the antibody binds to mesothelin, carrying an agent that targets tubulin. That’s how it can specifically target the cancer cells. This approach has not been successful as a single therapeutic agent in mesotheliomas. That is the rationale as to why this approach is being combined with doxorubicin in a clinical trial for patients with platinum-resistant ovarian cancer.
The second approach takes a very similar idea: using antibody-directed therapies to target the folate receptor alpha. The folate receptor alpha can be overexpressed in ovarian cancer, but it’s not expressed at high levels in normal tissue. Therefore, it makes it a potential target. Similarly, an antibody that targets the folate receptor alpha can carry a drug conjugate that is taken up by the cancer cells. This is being explored in a series of ongoing clinical trials.
The FORWARD I trial looked at utilizing this approach with mirvetuximab soravtansine compared with clinician’s choice of chemotherapy for patients with platinum-resistant ovarian cancer. It is now being looked at in phase Ib/II trials where it’s being tested in combination with bevacizumab (Avastin), carboplatin, or doxorubicin. One arm looked at patients with platinum-resistant ovarian cancer and another arm looked at patients with platinum-sensitive disease.
The challenge with a biologic approach is that it relies on the fact that all of the tumor cells express this antigen or target to some extent. This may not be the case. If a small subset of the tumor cells do not express this antigen, they may evade this therapy. If those cells can regenerate the cancer, the cancer can relapse.
While these approaches are exciting, I’m excited about approaches that target ubiquitous pathways in the tumor. One such pathway is targeting p53, which is coined “the guardian of the genome.” It plays a very central role in making sure that the cell does not undergo chaos. It does this by sending a stress. If the stress is small, it tells the cell to repair DNA damage and the cell goes on to live. If the stress is severe, the cell then undergoes death. When it is mutated, it cannot do those normal functions.
It is a very exciting target to try to restore the p53 function, but to this day we don’t have an FDA-approved drug that can target p53.
There are 3 approaches that are being taken to restore p53 function. Many of these approaches are focused on restoring the folding of p53. In order to function properly, it has to be a tetramer and properly folded, so it can bind to DNA.
APR-246 is one of the first drugs being tested. It was found in a drug screen, speci cally targeting cells that carry a kind of p53
mutation. It is an interesting compound, but it has to be converted to methylene quinuclidone. The compound then binds to cystines in either p53 or any molecule that carries a cystine. By doing so, it’s thought that it can restore the folding and function of p53.
This is being tested in clinical trials in combination with other agents. One of the challenges is that the exact mechanism of action is not known. Therefore, biomarkers of response need to be discovered.
A second compound that is in clinical trials is a zinc-specific chelator. For p53 to be properly folded, it requires the right amount of zinc around it. Zinc chelators are thought to modulate p53 function folding by binding to zinc. This compound is also being tested in phase I clinical trials in ovarian cancer and heavily pretreated head and neck cancers.
One of the approaches that we are very excited about is using peptides to restore p53 function. It’s known that a subset of p53
mutations cause amyloid sheets to form. p53
mutations can cause this aggregation. They can stick to each other, aggregating amyloid sheets, so it cannot function normally.
We work with a brilliant group of collaborators at UCLA led by the lab of Drs David Eisenberg and Alice Soragni. They discovered a peptide that specifically targets a portion of p53 that is highly prone to this aggregation process. The peptide can sit at the groves of mutated p53
so newly synthesized [p53] can potentially be free to do its function. It also has a polyarginine tag that lets it get into the cell.
In collaboration with this group of scientists at UCLA, my lab has been doing a lot of preclinical testing. We are looking at the e cacy of what we call the “reactivator of p53” using a combination of in vitro and in vivo models. The ndings are promising; it certainly has efficacy as a single agent.
Now we are looking at combining it with carboplatin, which is a standard therapy for ovarian cancer. We want to see if these 2 drugs together can be synergistic. Since we know what the peptide’s mechanism of action is, we’re looking at biomarkers of response. We hope to be able to transition this to clinic soon.
Does doxorubicin hold the most promise in combination with antibody-drug conjugates?
Doxorubicin is used in many clinical trials because the patients who are enrolled in these trials are patients with platinum-resistant disease. It makes sense to use one of the most commonly used second-line agents.
Do you see the preclinical work transitioning to the clinic soon?
That’s our hope. We are actively working on pushing this project forward. It’s certainly a collaboration between different groups at UCLA. That is what is so exciting about science. We hope to be able to transition this to clinic within the next year or two. Sometimes translational science takes longer than you anticipate, but we clearly see efficacy. Most importantly, it seems to be well tolerated in the in vivo models.