Moffitt Cancer Center

The number of new cancer treatment options has increased tremendously over the past 20 years, resulting in significant improvements in patient outcomes. Despite these improved therapies, most patients will eventually develop drug resistance and disease recurrence. Scientists continue to develop new drugs and drug combinations to overcome resistance, but the cycle often continues with patients developing resistance to these therapies, as well. Researchers in Center of Excellence for Evolutionary Therapy at Moffitt Cancer Center are thinking outside the box and studying an alternative approach called adaptive therapy that is based on evolutionary principles and mathematical modeling. 

In a new article in eLife, the researchers report updated results from a pilot clinical trial evaluating an adaptive therapy approach using the drug abiraterone to treat patients with metastatic castrate-resistant prostate cancer.

The Moffitt team developed their clinical trial based on a hypothesis guided by evolutionary principles; while resistance will develop in all tumors, not all resistant cells will have the ability to grow and survive because they need to compete with sensitive cells for limited resources. Therefore, the researchers’ goal was to maintain a population of drug sensitive tumor cells that could keep resistant cells in check through competition.

“Evolution-based models show current treatment strategies, which apply therapy at maximum tolerated dose until progression, are often not evolutionarily optimal,” said Robert Gatenby, MD, co-director of the Center of Excellence for Evolutionary Therapy. “While an initial response may be large, therapy fails because it strongly selects for resistance while eradicating all treatment sensitive cells. The resistant cells are now free from competition with sensitive cells, an evolutionary dynamic termed ‘competitive release,’ which allows for rapid proliferation.”

Rather than using a conventional treat until progression approach, Moffitt researchers wanted to investigate the potential benefits of an adaptive therapy approach that bases the dose and timing of a drug on a patient’s response to therapy. They conducted a pilot clinical trial in 17 patients with metastatic castrate-resistant prostate cancer. Treatment with abiraterone was discontinued when a patient’s biomarker PSA levels decreased by more than 50% of baseline levels. When a patient’s PSA levels increased again, abiraterone treatment was reinitiated, and the cycles of biomarker testing and drug withdrawal/retreatment continued. The feasibility and clinical benefit of the adaptive abiraterone therapy was reported in Nature Communications in 2017.

In this updated analysis with four additional years of follow-up, they found that patients treated with the adaptive therapy approach had a significantly longer median time to development of cancer progression (33.5 months vs. 14.3 months) and a longer overall survival (58.5 months vs. 31.3 months) than patients treated with the standard continuous treatment until progression approach. All patients treated with the standard approach developed progressive disease and died by the time of the report, but four patients on the adaptive therapy approach still have no evidence of progression and are alive. Importantly, patients treated with adaptive therapy were off treatment 46% of the time during the trial, which can reduce drug side effects and expenses. A recent economic analysis of the study found that this could reduce the average expense per patient by $70,000 per year.

The Moffitt team performed a follow-up mathematical analysis of the interactions between resistant and sensitive tumor cells and identified strategies to further improve patient outcomes. Their analysis revealed that every patient in the control group could have benefited from the adaptive therapy approach. Furthermore, they discovered that delaying the withdrawal of abiraterone resulted in the death of too many drug sensitive cells, which resulted in higher levels of resistant cells and poorer patient outcomes. This often occurred because radiographic imaging took place several months after changes in PSA levels, leading to delays in drug withdrawal. The researchers believe that addressing these trial design issues could lead to even better patient outcomes in future adaptive therapy trials in prostate cancer patients.

“These analyses illustrate the critical role for inclusion of mathematical models, evolutionary first principles and computer simulations in trial design. Unlike conventional clinical trials, this approach allows both cohort and patient-specific analyses. Furthermore, the simulations critique trial design and performance thus providing guidance for alternative strategies and future investigations,” said Jingsong Zhang, MD, PhD, principal investigator of the adaptive therapy trial and associate member of the Genitourinary Oncology Department at Moffitt.

This study was supported by the National Cancer Institute (R01CA170595, U54CA143970, P30-CA076292), the James S. McDonnell Foundation, the Jacobson Foundation and the European Union’s Horizon 2020 research and innovation program (No. 690817).

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“These analyses illustrate the critical role for inclusion of mathematical models, evolutionary first principles and computer simulations in trial design. Unlike conventional clinical trials, this approach allows both cohort and patient-specific analyses," said Jingsong Zhang, MD, PhD.

Moffitt study shows adaptive therapy improves outcomes, reduces care costs for prostate cancer patients

Prostate cancer is the most common cancer among men in the United States. Many patients can live long lives due to early detection and treatment with androgen deprivation therapy. However, despite the benefits of this therapy, almost all patients will eventually develop drug resistance and recurrent disease. In a 

 published in Science Translational Medicine, Moffitt Cancer Center researchers reveal a mechanism by which prostate cancer cells become resistant through molecular modification of the androgen receptor protein and identify a potential treatment approach that could overcome this resistance.

Androgen deprivation therapy has been the mainstay of prostate cancer treatment for decades. The goal of this therapy is to reduce the levels of hormones called androgens that stimulate prostate cancer cell growth through either surgical or medical approaches that target androgen receptor signaling. Androgen deprivation therapy greatly improves survival, but almost always leads to recurrent disease called castration-resistant prostate cancer. Scientists have discovered that resistance is primarily due to re-activation of androgen receptor signaling through different mechanisms, and they developed new drugs, such as enzalutamide and abiraterone, to overcome this resistance. Unfortunately, patients also eventually develop resistance to these drugs in a relatively short period of time. Several resistance mechanisms to these newer-generation drugs have been identified, but these modifications are not present in all patients, suggesting that additional resistance mechanisms exist.

The Moffitt research team, in collaboration with scientists at Washington University in St. Louis, wanted to identify alternative resistance mechanisms to enzalutamide and abiraterone in prostate cancer patients. They performed a series of laboratory experiments focused on the molecular modifications of the androgen receptor and its interactions with other proteins and DNA. They discovered that the androgen receptor becomes chemically modified at two distinct sites. First, a phosphate group is added to the androgen receptor protein by a protein called ACK1. This chemical modification permits a second modification, during which an acetyl chemical group is added. This modification occurs on a location of the androgen receptor that enables it to become active, even in the presence of enzalutamide. These combined events result in a positive feedback loop during which the androgen receptor further increases levels of itself, as well as the ACK1 protein.

The researchers confirmed the importance of these molecular modifications in mouse experiments. They demonstrated that treatment of enzalutamide/abiraterone-resistant prostate tumors in mice with a Moffitt-designed ACK1 inhibitor called (

)-9b that targets ACK1 suppressed tumor growth, and reduced expression levels of ACK1, the androgen receptor and additional key genes regulated by the androgen receptor. Importantly, the researchers also showed that the expression level of ACK1 and the modified androgen receptor were higher in tissue samples from patients with prostate cancer than normal prostate tissue, and their expression increased throughout cancer progression.

“These combined observations suggest the importance of these androgen receptor modification events and protein interactions to the development of castration-resistant prostate cancer,” said Nicholas Lawrence, Ph.D., study co-author and senior member of the Drug Discovery Department.

“Identification of an ACK1 kinase inhibitor that has the ability to thwart both the modifications, and the fact that an ACK1 inhibitor has not yet advanced to clinical trials, these data could open a new therapeutic modality for recurrent castration-resistant prostate cancer patients, a currently unfulfilled need,” added Harshani Lawrence, Ph.D., study co-author and scientific director of Chemical Biology.

Drs. Nicholas and Harshani Lawrence, both medicinal chemists, are the inventors of (

This study was supported by grants received from the National Institutes of Health (R01CA208258, R01CA227025, R50CA211447), the Prostate Cancer Foundation (17CHAL06) and the Department of Defense (W81XWH-15-1-0059).

The Moffitt research team, in collaboration with scientists at Washington University in St. Louis, wanted to identify alternative resistance mechanisms to enzalutamide and abiraterone in prostate cancer patients.

Moffitt researchers contribute to discovery of mechanism leading to drug resistance in prostate cancer

Chimeric antigen receptor T-cell therapy, or CAR T, has made a big impact on the treatment of certain blood cancers, allowing patients with relapsed/refractory disease to live longer, healthier lives. But in clinical study, the cellular therapy has not been as successful for patients with solid tumors, due in part to the lack of tumor targets not expressed in vital tissues. In a 

, a journal of the American Association for Cancer Research, Moffitt Cancer Center researchers share the identification of a new potential target for CAR T cells called OR2H1 that they have demonstrated inhibits growth in lung and ovarian tumors.

The key to CAR T-cell therapy is the genetic modification made to the patient’s T cells. Their cells are collected through a process called apheresis, and then shipped to a laboratory where the cells are modified to contain a gene for the T cell receptor that recognizes a specific marker on cancer cells. Those modified T cells, now CAR T cells, are stimulated to grow and multiply before being sent back to the hospital to be infused back into the patients. The receptor on the CAR T cells acts as a GPS, seeking out their specific marker on the surface of the cancer cells. Currently there are CAR T therapies approved to treat patients with lymphoma, leukemia and multiple myeloma, but there are no approved CAR T therapies for solid tumors.

Moffitt researchers are working to identify tumor markers that can make CAR T an effective therapy for patient with solid tumors. The goal is to find a marker that is expressed on tumor cells but not on normal cells, to reduce the potential for unwanted toxicities. The team, led by Dr. Jose Conejo-Garcia, focused the search on a family of proteins called olfactory receptors that are expressed in the nose and contribute to the perception of smell. During lab experiments, they discovered that the protein OR2H1 is expressed in a variety of solid tumors, ranging from 4% of colon cancer samples to 69% of cancers of the gall bladder. Importantly, of all normal tissues examined, OR2H1 was found only in the testis, suggesting that therapies that target OR2H1 would have minimal effects on normal cells.

The researchers then created CAR T cells that were specific to the OR2H1 protein. The OR2H1 CAR T cells were able to kill lung and ovarian cancer cells that expressed OR2H1 but had no effect on healthy cells. The OR2H1 CAR T cells also had anti-tumor effects in vivo in immunodeficient mice challenged with human tumors. Tumor inhibition was observed in lung and ovarian cancer mice models with varying levels of OR2H1, including ovarian cancer cells that were resistant to chemotherapy.

These combined data suggest that OR2H1 may be an effective target for CAR T therapies in solid tumors. The researchers hope these initial studies will lead to the development of OR2H1 CAR T cells for a wide variety of patients with solid tumors.

“Our work demonstrates the applicability of this therapy to a wide variety of patients, given the expression of OR2H1 in a subset of solid tumors across multiple histologies, including high-grade serous ovarian cancers, lung carcinoma, cholangiocarcinoma, prostate cancer and ovarian cancers of multiple other histologies. Targeting a molecule that is not expressed in vital tissues would allow us to further engineer T cells to overcome immunosuppression at tumor beds, if needed,” said Conejo-Garcia, chair of Moffitt’s Department of Immunology.

This work was supported by the National Cancer Institute (P30CA076292, R01CA157664, R01CA124515, R01CA178687, R01CA211913, U01CA232758, T32CA009140, K99CA266947), the Moffitt Foundation, Moffitt’s Junior Scientist Research Partnership Award and the American Cancer Society Postdoctoral Fellowship.

Prostate tumors are among the cancers for whom this novel therapy is being explored.

Moffitt Cancer Center

Articles

Moffitt study shows adaptive therapy improves outcomes, reduces care costs for prostate cancer patients

Moffitt researchers contribute to discovery of mechanism leading to drug resistance in prostate cancer

Moffitt researchers discover new target for CAR T-Cells in solid tumors