1. Can you tell us about yourself and what led you to work in the breast cancer field?
One key lesson I have learned early in my career is that targeted therapies work for the treatment of breast cancer. I witnessed this first-hand when breast cancer hit my family. When I was in graduate school, my Grandmother was diagnosed with breast cancer and the idea of her having breast cancer was scary. However, we soon learned that there was a targeted therapy to treat her type of breast cancer, so she was one of the lucky patients. She took tamoxifen for five years and lived a full life to the age of 94 years old. Tamoxifen was the first targeted therapy developed for breast cancer, which works by targeting the estrogen receptor (ER). Approximately 70% of all breast cancers express ER. Tamoxifen and related selective estrogen receptor disruptors (SERDS), which block ER, have taken what was originally thought of as a death sentence for patients 30 years ago and changed it into a manageable disease. The proven success of SERDS for the treatment of breast cancer is remarkable, however there is still much more work to do in the area of breast cancer therapeutics. What interested me most was developing targeted therapies for women who are not as fortunate as my Grandmother, but for whom through precision medicine efforts, will benefit as she did.
I have spent the past 30 years in the field of breast cancer research, and for me the one area I am most passionate about is triple-negative breast cancer (TNBC) because it disproportionately impacts young women who are in the prime of their lives. I hope that in the future, we will see the same level of success in TNBC as we have seen in the treatment of other types of breast cancer.
2. While researchers have made great progress in the treatment of breast cancer, the TNBC subtype remains an aggressive, difficult-to-treat disease. Can you explain why this is in disease mechanistic terms?
The primary reason TNBC is so hard to treat is that there remains a lack of targeted therapies specifically for this type of breast cancer. Unlike the other breast cancer subtypes, TNBC lacks the receptors which we can target with the current approved targeted drugs for breast cancer. Drugs such as tamoxifen do not apply given that TNBC does not express the ER and progesterone (PR) receptors. TNBC also lacks Her-2, a kinase that drives the growth of approximately 15% of breast cancer. The lack of ER, PR and Her-2 means that patients are ineligible for targeted therapies that attack thoseproteins. It is therefore important to understand what uniquely drives the growth of TNBC.
Another reason that TNBC is so hard to treat is because the disease is heterogeneous. TNBC tumors are made up of diverse subsets of cancer cells, making it that much more challenging to find an effective target to develop a treatment against. Understanding this about TNBC has prompted the search for molecular drivers that are common denominators despite the heterogeneity. The primary way in which drug developers have identified ‘hits’ for TNBC is through unbiased functional screens using gene silencing tools such as siRNA, shRNA or CRISPR. This is exactly how we, and several other groups, independently identified RSK2 (ribosomal S6 kinase 2) as a driver of TNBC. In a screen representing TNBC heterogeneity, we found that RSK2 knockdown inhibited tumor growth and induced cell death. Immunohistochemical analysis shows that the expression of RSK2 is uniformly activated in primary TNBC as well, reinforcing it as one of the common denominators associated with this heterogenous disease. RSK inhibitors, as a result, have been at the forefront of therapeutic targeting for TNBC. We developed PMD-026, which is the first orally available small molecule that inhibits RSK2. In a first-in-human Phase 1 clinical trial, we evaluated the safety of PMD-026 in women with metastatic breast cancer where we found it was generally well-tolerated. Given these promising results, we are excited to have launched our Phase 1b expansion trial in women with TNBC at multiple leading medical centers in the United States (NCT04115306).
3. Patients with TNBC have a poor prognosis in large part possibly because treatment strategies have developed slowly. Four new subtypes of cells within TNBC have recently been unearthed by researchers at Garvan Institute of Medical Research containing promising new therapeutic targets. Which requirements should investigators and drug companies consider for the optimization of translational value?
I think the identification of new subtypes again reinforces the heterogeneity of TNBC. However, whether there are four subtypes identified or ten, the translational value rests on actionable targets. Many targets are not actionable because they are not druggable, which is why we focused on targeting kinases which has a long history of success in precision medicine. The approach that Wu et al took at the Garvan Institute was an interesting one because it looked at the stromal components of TNBC for clues to new targeted approaches. See https://doi.org/10.15252/embj.2019104063
They identified CXCR12, which is a cytokine found in one of the stromal TNBC subtypes and this could be actionable by either blocking the cytokine itself or its receptor CXCR4. Innovations such as this may move our field forward.
4. Numerous approaches involving targeted therapies have gained recent recognition; these include poly ADP ribose polymerase (PARP) inhibitors, immune checkpoint inhibitors, and combination approaches, so what are the key strategies being investigated in clinical trials to improve upon currently available treatment?
Combinations, combinations, combinations- this is the strategy that has really moved the needle in breast cancer therapeutics over the past 5 years. We are going to see more of this as we build on proven success. A great example of this is the targeting of CDK4/6 and ER which has led to improved outcomes for women with hormone positive metastatic breast cancer. There are now at least three approved drugs that target CDK4/6 and I suspect there will be more to come. One of the pressing questions many of us have in the field is which combinations will give immunotherapies the best chance of success. This is an area where there is heavy traffic right now in combination therapeutics. In TNBC the combination strategy has never been more obvious as approved therapies are still only providing limited clinical benefit.
5. Which agents in late phase clinical trials hold particular promise for TNBC?
One of the most exciting new advances in late phase clinical trials for TNBC is sacituzumab govitecan-hziy (sacituzumab govitecan), a first-in-class antibody conjugated drug that takes aim at Trop-2 on the cell surface and then delivers a chemotherapy payload (SN38) to the cancer. In a late breaking abstract presented at the European Society for Medical Oncology virtual congress 2020, Aditya Bardia MD from Harvard Medical School reported the results from the Ascent clinical trial (Abstract# LBA17). In TNBC patients who had four prior lines of therapy, sacituzumab govitecan improved their overall survival (OS) by 5.4 months. It provided a median OS of 12 months as compared to chemotherapy, which afforded a median survival of 6.7 months, HR, 0.48; P < 0.0001. Sacituzumab govitecan also showed improvements in progression free survival (PFS) with a median PFS of 5.6 mo vs 1.7 mo for patients taking chemotherapy; HR, 0.41; P < 0.0001. The trial was stopped early because the results were so promising. This is the most significant advance in our field in some time. The overall response rate was 35% which in this difficult disease is notable. In the future, there will be opportunities to evaluate combination therapies with sacituzumab govitecan to further improve patient outcomes for women with TNBC.
6. Can you tell us something about the importance of companion diagnostics and how they could enhance clinical trials and future treatments?
Companion diagnostics (CDx) should be the cornerstone for new therapies because as we have learned over the years, one size does not fit all. Being able to deliver precision medicine to patients that will benefit the most is a standard we ought to uphold. There is proven success in CDx guided therapies, which we first saw with ER detection and the use of SERDs and then later with Her-2 detection and the use of therapies such as trastuzumab. In less common types of breast cancer which have a hereditary component to them, we have seen success in the use of PARP inhibitors for cancers with BRCA1/2 mutations. In TNBC, we have RSK2 activation coupled with our RSK inhibitor, PMD-026.
7. Can you elaborate on the agents that are about to enter clinical development at Phoenix molecular?
Because RSK2 is a driver of drug resistance in multiple cancers, we are interested in unlocking our platform technology to evaluate combination therapies as the next stage of our clinical development plan. Generally, combination therapies have been center-stage for the treatment of breast cancer. We have seen, for example, how the combination of CDK4/6 inhibitors with hormone therapies have improved the management of metastatic ER positive breast cancer. Going back to the heterogeneity of TNBC for just a moment, we expect that it will be combination therapies that will make true progress. We certainly saw this with immuno-oncology therapies such as atezolizumab, which alone was not enough to combat TNBC. However, when combined with nab-paclitaxel, it provided benefit to a subset of patients. Likewise, we find that TNBC has variable sensitivity to paclitaxel alone in several preclinical models. However, by adding PMD-026 to paclitaxel, we can optimally inhibit the growth of primary patient-derived xenografts by ~80%. We also believe there is an opportunity to combine PMD-026 with several other therapies for the treatment of breast cancer as we have identified synergies in preclinical studies with numerous therapies including chemotherapy, hormone therapy and potentially immunotherapies.
8. TNBC patients lack treatment options and experience poor outcomes. A significant number of these patients die within 5 years of diagnosis, but which patient-related outcomes do you see as key in the assessment of treatment and aftercare?
As we are in the middle of a global COVID-19 pandemic, at the top of my wish list are therapies that protect the immune system of the cancer patient. Unfortunately, chemotherapy can have damaging effects on the immune system which puts cancer patients at a disadvantage when it comes to fighting infections such as COVID-19. The push for targeted therapies has never been greater, particularly given the immune sparing properties that are a distinct advantage that targeted therapies have over traditional treatments for TNBC.
Patient quality of life is also at the top of my list. The cancer journey for women can be a long and arduous one and the fact that this disease impacts younger women in the prime of their life is something that gives our work added significance. I would like to see therapies that have minimal side-effects so that women can continue to live their lives and do the things that they could do prior to receiving therapy. Their well-being should be preserved during treatment. Therapies that do not cause hair loss or peripheral neuropathy are high on my list.
9. What are your hopes for the diagnosis and treatment of patients with TNBC over the next decade?
I am hoping that we can find new ways to detect TNBC in younger women and raise awareness among younger women about being in control of their breast health.
The real challenge is a lack of suitable imaging techniques because it has been shown that mammograms are less effective for young women. Therefore, early detection especially for TNBC patients is key because the sooner we can diagnose the disease, the quicker we can treat it and increase their chances for survival. I would also like to see more routine genetic testing done for young women because, together with family history, more personalized advice on breast cancer risks and possible lifestyle changes and prevention measures can be discussed. Additionally, a more comprehensive look at novel therapies is a must when matched to the specific molecular cancer type of the patient using CDx. Ideally, I want to see therapies that are curative and durable so that patients with TNBC can put breast cancer in their rearview mirror.
Declaration of interestpt
SE Dunn is employed by Phoenix Molecular Designs. SE Dunn has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.