The current status of treatment for advanced bladder cancer is not ideal. Chemotherapy in this setting is at most moderately effective – neoadjuvant chemotherapy (NAC) achieves complete responses in <40% of patients. Even in the metastatic setting, it has 50% response rates in the primary setting and <10-20% in the salvage setting.
The current approach to identifying chemoresistance is to study individual genes or gene panels – which, while helping to understand chemoresistance mechanisms, is not always clinically useful. As there are over 700 genes involved, a single gene or panel of genes will unlikely even give a broad representation. As such, they have decided to look at more of a pathway approach.
In the platinum-chemotherapy induced cell damage, they hypothesized that the DNA damage step is the most critical. Levels of drug-DNA damage therefore may help predict resistance to chemotherapy. Several studies have already demonstrated that low DNA damage correlates to chemoresistance. Unfortunately, the technology to measure DNA damage are not sensitive – and were limited to measuring it after chemotherapy administration, which is not clinically useful.
They have now had access to the Accelerated Mass Spectrometer (AMS). It has a very high sensitivity to detect 14C (used for carbon dating). Patients are treated with one microdose of 14C and AMS can then be used to measure DNA damage and chemoresistance.
They found that low DNA adduct levels correlated with chemoresistance in bladder and breast cancer. This was primarily done in bladder xenograft models (mouse models). Based on this, they moved to a phase 0 microdosing study.
In this, they found that microdosing predicts pharmacokinetics of therapeutic dosing. High DNA adducts and DNA damage were associated with chemosensitivity. This is very interesting work!
Moving on to his next topic, he focused on cancer nanoparticles. He compared this with a “bullet vs. missile” approach – conventional chemotherapy are like bullets, which nanoparticles are like missiles. Essentially, these are therapeutic agents that are linked to cancer-specific receptors and packaged and nanoparticles. In vitro tumor activity (mouse xenograft models) was significantly higher than conventional chemotherapy administration. Obviously, there are a lot of potential applications for this!
One such application is photodynamic therapy (PDT). In this case, PLZ4-nanoporphyrin delivers the photodynamic agent directly to the bladder cancer. With PDT, the agent is activated and works only on bladder cancer tissue. It kills cancer cells and releases cancer antigens – and as such, may be able to used in conjunction with immunotherapy to potentiate response! He presented preclinical data that appeared very promising – mice treated with anti-PD1 antibody and PDT did better than mice treated with either in isolation.
Presented by: Chong-Xian Pan, MD, PhD, MS, University of California Davis
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, @tchandra_uromd at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA