Prostate cancer is a leading cause of cancer death for men worldwide—it took the lives of nearly 27,000 men in the United States alone in 2016. Part of the problem is that patients often develop degrees of treatment resistance. And for a small percentage of patients, a transformation occurs: an entirely treatment-resistant, aggressive form of the cancer evolves and grows as the original recedes.
Under the microscope, these new cancer cells start to look less like the most common type of prostate cancer, prostate adenocarcinoma. Instead, they develop characteristics that look more like small-cell neuroendocrine cancer.
“As you potently target a key pathway in cancer—in prostate cancer, the androgen receptor signaling pathway—other pathways can emerge. This lineage plasticity evolves as a way for the cancer cells to evade therapy,” says Himisha Beltran, Medicine, Weill Cornell Medicine. Beltran first observed this aggressive form of cancer in the clinic.
“As treatments for prostate cancer improve, and patients are living longer, we’re starting to see a changing landscape of patients in the clinic,” she says, “and we’re realizing that once patients evolve to neuroendocrine prostate cancer, it tends to spread to places that the classic cancer doesn’t, and it’s harder to treat.”
Leading an interdisciplinary team of scientists and clinicians, Beltran investigates how treatment resistance develops in prostate cancer, how to detect neuroendocrine prostate cancer evolution, and how the medical community can try to stop it.
How Prostate Cancer Evolves To Resist Treatment
The most common form of prostate cancer is an adenocarcinoma. It is often treated by interfering with the androgen receptor-signaling pathway. “We know prostate cancer is a hormonally driven disease. But despite effective drugs that target the androgen receptor, advanced prostate cancer continues to develop ways to restore androgen receptor signaling,” Beltran says.
The drivers are not the same for neuroendocrine prostate cancer. “What we found is that these new tumors are no longer driven by androgen receptor signaling. Other pathways become activated,” Beltran says. “The cancers develop new genomic and epigenetic alterations, and there is some overlap at the molecular level with other aggressive neuroendocrine cancers, such as small-cell lung cancers.” It follows that patients who have evolved to this new cancer will not respond to hormonally-based therapies.
Beltran took her observations back to the lab to understand the mechanisms underlying this cancer evolution and to develop better ways to treat neuroendocrine prostate cancer. “Since it is an evolution from one disease state to another, which doesn’t happen overnight, there’s also an opportunity to detect patients in transition, to be able to develop new treatment strategies in that space,” Beltran says.
One of the problems, however, is that the main diagnostic tool is currently biopsy, which is invasive, carries some risk and is usually only performed once—at the time of a patient’s initial diagnosis. To track this evolution of treatment resistance over time, a new tool is needed.
In studying the differences between the two types of cancers, Beltran and her collaborators at University of Trento have found that the molecular features of neuroendocrine prostate tumors may be detectable in tumor DNA that circulates throughout the blood. With this profiling, Beltran is now working on ways to detect neuroendocrine prostate cancer early, using a non-invasive blood test.
The Search for New Therapeutics
Early detection may allow for a change in the course of treatment before it’s too late. But a key question remains: what is the treatment for this form of prostate cancer?
“As you potently target a key pathway in cancer…other pathways can emerge. This lineage plasticity evolves as a way for the cancer cells to evade therapy.”
In early studies, Beltran identified an essential protein, N-Myc, as highly expressed in neuroendocrine prostate cancer. She found that N-Myc is capable of promoting treatment resistance and driving the development of the cancer. Since then, working with Weill Cornell Medicine colleague David S. Rickman, Pathology and Laboratory Medicine, their team has developed a mouse model to better understand how N-Myc contributes to the disease.
With this model, Beltran has also been working on how to target N-Myc. “It is a difficult protein in itself to target, so we’ve been looking at targeting it indirectly,” she says. “One approach is to target a protein that stabilizes N-Myc, which is called aurora kinase A.”
This work led her to initiate an ongoing, multi-center, phase 2 clinical trial looking at a drug, alisertib, that disrupts the N-Myc-aurora kinase complex and inhibits N-Myc signaling. “In preliminary results, we found some patients with neuroendocrine prostate cancer had extraordinary responses to the drug,” Beltran says. “As with most trials, one of the disappointments was that not everybody did.”
The trial has provided a wealth of information that Beltran is now mining. “Using data from the patients in the trial as well as developing model systems from metastatic biopsies from those patients, we’ve been able to delve deeper into understanding why certain patients responded and others didn’t. We are also using this information to develop new therapeutic strategies,” she says.
In collaboration with Rickman and Mark A. Rubin, director of Weill Cornell Medicine’s Englander Institute for Precision Medicine, Beltran and her team are currently working on new pharmacologic ways to disrupt and inhibit the N-Myc-aurora kinase pathway. She is also designing experiments to understand how N-Myc cooperates with other molecular alterations that occur during neuroendocrine prostate cancer’s progression. Using this data, she is developing new targeted and immune approaches to treat or even reverse the cellular plasticity process that can lead to treatment resistance.
Matching Patients with Therapies—Precision Medicine
Beltran’s focus on the genetic and molecular features of the cancers that she studies reflects a trend in cancer research. “Precision medicine is an approach to match the best therapeutic with the right patient based on the molecular profile of that patient’s cancer. The approach recognizes that one therapy may not work the same in different patients even within the same tumor type and that cancers can evolve during the course of the disease. This is a concept that extends beyond prostate cancer,” she says.
The Englander Institute for Precision Medicine, where Beltran directs clinical activities, is a leader in the effort to improve and personalize clinical care and treatment. “Our goal is to bring cutting-edge genomic sequencing technologies into routine cancer care. We use this information to inform rational treatment recommendations and clinical trials,” Beltran says.
“We now have the capability to look at cancers better than ever before,” Beltran continues, “so we want to use this data to start asking bigger questions—why do some patients respond to treatment and others don’t? Are there targetable alterations relevant across cancer types? What genetic factors influence why a patient gets cancer in the first place, or how well they do once cancer develops?”
As the capability to study human disease improves, Beltran says there’s more opportunity for the translation of basic science to the clinic. “In the past, basic science and clinical medicine were not as closely intertwined,” she says. “But we have new tools to deeply profile cancers, develop model systems, understand cancer genetics and tumor biology, and to develop new treatments faster. I think it’s a great opportunity for translational researchers and physician-scientists to make an impact.”
This is exactly what Beltran has always set out to do—to bridge the divide between research and patient care. “While it does require managing time and speaking different languages, I think it is exciting and empowering,” she says. “My patients motivate me and drive my research. Being engaged in research also helps me bring the latest technologies and new therapies back to my patients. Our patients get involved and participate in research, in trials. It is rewarding to be at that interface.”
The interdisciplinary environment and the research infrastructure at Weill Cornell Medicine make it possible. “Being able to work with a range of investigators with expertise across disciplines, to ask questions in different ways—this is why I chose Cornell,” Beltran says. “It’s a collaborative environment that facilitates translational research and helps me effectively bridge the clinic and the laboratory.”