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.