Advances in UCLA Prostate Cancer Research and Treatment
Prostate cancer remains a significant health concern for men. The UCLA Prostate Cancer Program is at the forefront of research and treatment, offering innovative options and striving to improve patient outcomes. This article delves into recent advancements, ongoing research, and the multidisciplinary approach that defines UCLA's commitment to combating prostate cancer.
Understanding Prostate Cancer Evolution: A Key to New Therapies
As cancers progress and spread, they often become more aggressive, developing resistance to treatments. Researchers at UCLA have made a significant breakthrough in understanding how a common type of prostate cancer transforms into a more aggressive variant known as small cell neuroendocrine (SCN) cancer.
In a study published in Cancer Cell, Dr. Owen Witte and Dr. Thomas Graeber co-led a research team that meticulously recorded the molecular steps involved in this transformation. The study provides a real opportunity to define the process that leads to these very aggressive tumors. SCN cancers constitute a small percentage of newly diagnosed prostate cancers but are more prevalent in tumors that persist after treatment. These cancers are characterized by their rapid growth and resistance to therapy.
The researchers used a novel model where healthy human prostate cells were implanted into mice and then engineered to become adenocarcinomas, eventually progressing to SCN cancers. The ability to track this progression from normal cells provided a unique advantage in understanding the changes occurring at each stage. Biopsies were collected every two weeks for at least ten weeks, and detailed analyses were performed to identify the genetic programs activated at each time point.
The team discovered that prostate adenocarcinomas follow two predictable paths to evolve into SCN cancers, and are planning future studies to develop methods to block these newly discovered evolutionary pathways. Several of the identified molecular changes critical for SCN cancer evolution have the potential to be targeted with drugs. Rather than focusing on treating full-blown SCN prostate or lung cancers, the researchers suggest that drugs could be developed to block the progression of less aggressive subtypes, preventing SCN cancers from arising.
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This reproducible process highlights how cancers become more aggressive, and predicting this progression may allow for preventative measures.
Innovative Treatment Approaches at UCLA
UCLA offers a wide range of treatment options for prostate cancer, tailored to each patient's specific condition. These options include:
- Robotic Surgery: UCLA Urology has been a leader in robotic surgery since 2004, with high-volume surgeons who have led the technical advances in the field. They also offer outpatient prostatectomy and are using an innovative single-port (SP) (one small incision) robotic system for the most advanced minimally invasive robotic prostatectomy.
- MRI-Targeted Biopsy: UCLA utilizes advanced MRI imaging techniques for targeted prostate biopsies, ensuring the most accurate diagnosis and treatment planning.
- Precision Medicine: The Institute of Urologic Oncology at UCLA offers precision medicine approaches, including genomic testing and advanced biopsy techniques, to guide treatment decisions in metastatic and castration-resistant forms of prostate cancer.
- Telemedicine: The UCLA Urology Telemedicine Expert Second Opinion Program provides California residents with access to faculty who are national leaders in all aspects of urology.
Clinical Trials: Advancing the Future of Prostate Cancer Treatment
UCLA is actively involved in numerous clinical trials aimed at developing new and more effective treatments for prostate cancer. Some of the ongoing trials include:
- 99mTc-PSMA-I&S Biodistribution in Patients With Prostate Cancer: This study investigates the biodistribution of 99mTc-PSMA-I&S, a PSMA-targeted radio-guided surgery technique, to detect prostate cancer spread to lymph nodes.
- Ifinatamab Deruxtecan (I-DXd) in People With Metastatic Prostate Cancer (MK-2400-001): This trial evaluates the effectiveness of ifinatamab deruxtecan in treating metastatic castration-resistant prostate cancer (mCRPC).
- FG-3246 in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC): This study assesses the safety and efficacy of FG-3246, an antibody-drug conjugate, in treating mCRPC patients who have progressed after prior androgen receptor signaling inhibitor treatment.
- Opevesostat (MK-5684) Versus Alternative Next-generation Hormonal Agent (NHA) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Post One NHA (MK-5684-004): This trial compares the efficacy and safety of opevesostat plus hormone replacement therapy to alternative treatments in mCRPC patients previously treated with a next-generation hormonal agent.
- Radiation Dosimetry, Safety, and Tolerability of Extended Lutetium (177Lu) Vipivotide Tetraxetan Treatment in Chemo-naïve Adults With Metastatic Castration-resistant Prostate Cancer: RADIOpharmaceutical DOSimetry Evaluation (RADIODOSE) Study: This study evaluates the dosimetry, safety, and tolerability of extended lutetium treatment in taxane-naïve adults with PSMA-positive mCRPC.
- Alpha-Emitting Radionuclide or Beta-Emitting Radionuclide With Metastasis-Directed Stereotactic Body Radiotherapy for the Treatment of Recurrent, Oligometastatic Prostate Adenocarcinoma: This phase II trial compares the use of 225Ac-PSMA-617 to 177Lu-PSMA-617, along with stereotactic body radiotherapy for the treatment of prostate cancer that has come back after a period of improvement (recurrent) and that has spread from where it first started (primary site) to multiple other places in the body (oligometastatic).
- Scan (Flotufolastat F 18 PET/CT) for Detecting Residual or Recurrent Disease in Patients Who Completed Focal Therapy for Prostate Cancer.: This phase II trial evaluates how well flotufolastat F 18 positron emission tomography (PET)/computed tomography (CT) imaging works to detect cancer that remains (residual) or that has come back (recurrent) after the completion of focal therapy for prostate cancer.
- Comparing a New PSMA Imaging Agent to MRI for Detecting Prostate Cancer, BEACON Trial: This early phase I trial evaluates whether a new imaging technique using flotufolastat F 18 (a type of prostate specific membrane antigen [PSMA] imaging agent) with positron emission tomography (PET)/computed tomography (CT) can be used to guide targeted prostate biopsies in men with prostate cancer.
- Computed Tomography-Guided Stereotactic Body Radiation Therapy With Intrafraction Motion Monitoring for the Treatment of Localized Prostate Cancer, ILLUSION Trial: This clinical trial studies the side effects of computed tomography (CT)-guided stereotactic body radiation therapy (SBRT) with intrafraction motion monitoring and to see how well it works in treating patients with prostate cancer that has not spread to other parts of the body (localized).
- Determining the Biodistribution of an Imaging Tracer (68Ga-FAPi-46) in Patients With Solid Tumors or Hematologic Cancers: This phase I trial is evaluating a new imaging tracer (68Ga-FAPi-46) with positron emission tomography (PET)/computed tomography (CT) to determine where and to which degree the tracer (68Ga-FAPi-46) accumulates in normal and cancer tissues (the biodistribution) in patients with solid tumors or hematologic (blood) cancers.
- FPI-2265 (225Ac-PSMA-I&T) for Patients With PSMA-Positive Metastatic Castration-Resistant Prostate Cancer (mCRPC): This is an open-label, randomized, multicenter study of FPI-2265 (225Ac-PSMA-I&T). Patient population is adult participants with PSMA positive mCRPC who have had previous treatment with with 177Lu-PSMA-617 or another 177Lu-PSMA radioconjugate (RC). The purpose of the study is to determine the safety and tolerability, and recommended dose and regiment of FPI-2265.
- High Dose-Rate Brachytherapy and Stereotactic Body Radiotherapy for the Treatment of Prostate Adenocarcinoma: This phase II trial investigates the effect of high dose-rate brachytherapy and stereotactic body radiotherapy in treating patients with prostate adenocarcinoma.
- Hormone Therapy (Apalutamide) and Image-guided Stereotactic Body Radiation Therapy for the Treatment of Patients With Prostate Cancer, HEATWAVE Trial: This phase II trial evaluates apalutamide in combination with image-guided stereotactic body radiation therapy (SBRT) for the treatment of patients with prostate cancer.
These trials reflect UCLA's commitment to exploring new avenues for prostate cancer treatment and improving patient outcomes.
Overcoming Treatment Resistance: A Focus on Stemness
UCLA researchers are also investigating the mechanisms behind treatment resistance in prostate cancer. A multi-institutional clinical trial shed light on why some advanced prostate cancers do not respond to drugs like enzalutamide.
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The trial compared the molecular blueprint of tumors that continued to grow following treatment with enzalutamide versus those that did not. The study found an underlying pattern of low androgen receptor activity and high stemness in the non-responsive tumors. This finding suggests that other, unknown factors are important in these cases.
The team plans to test drugs in the laboratory that are currently in pre-clinical testing, in clinical testing, or approved for use in other cancers that are predicted to block the stemness pathways implicated in their clinical trial. They plan to focus on tumor models that accurately reflect the biology of the patient tumors that did not respond to enzalutamide.
This research provides new clues about why enzalutamide may not work well to control certain prostate cancers and provides a new roadmap to test drugs that would not have otherwise been considered relevant. The ultimate goal is to identify drugs that can block this resistance program, leading to new clinical trials for patients with tumors inherently resistant to enzalutamide and similar drugs.
The Role of PSMA in Imaging and Therapy
Prostate-specific membrane antigen (PSMA) has emerged as a crucial target in prostate cancer imaging and therapy. UCLA has been a leader in the development and application of PSMA-targeted agents.
One notable achievement is the FDA approval of Gallium 68 PSMA-11 (68Ga-PSMA-11) for positron emission tomography (PET) imaging of prostate cancer. This imaging technique allows for more accurate detection and staging of prostate cancer, guiding treatment decisions.
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Furthermore, UCLA is involved in clinical trials exploring the use of PSMA-targeted radioligand therapy, such as 177Lu-PSMA-617 and FPI-2265 (225Ac-PSMA-I&T), for patients with metastatic castration-resistant prostate cancer. These therapies deliver radiation directly to cancer cells expressing PSMA, offering a more targeted and effective treatment approach.
Addressing Toxicity in Radiation Therapy
UCLA researchers are also focused on minimizing the side effects of prostate cancer treatment. A recent study, conducted by UCLA and other leading academic institutions, used MiraDx’s PROSTOX ultra test to identify prostate cancer patients at higher risk of late grade ≥ 2 genitourinary (GU) toxicity from stereotactic body radiation therapy (SBRT).
The findings confirmed that patients identified as genetically at high risk for toxicity after SBRT most frequently chose a different form of radiation therapy. These alternative approaches tended to be safe for them.
This research highlights the importance of personalized medicine in prostate cancer treatment, allowing clinicians to tailor treatment strategies based on individual risk factors.
A Legacy of Innovation and Discovery
UCLA's commitment to prostate cancer research and treatment is built on a strong foundation of innovation and discovery. UCLA researchers have been instrumental in developing groundbreaking therapies that have transformed the lives of cancer patients.
- Xtandi and Erleada: Developed by UCLA professor Michael Jung and Dr. Charles Sawyers, these drugs have significantly improved outcomes for patients with advanced-stage prostate cancer.
- Herceptin: Developed by Dr. Dennis Slamon, this drug revolutionized the treatment of HER2-positive breast cancer.
- Ibrance: Research led by Slamon and Dr. Richard Finn led to the development of Ibrance, a transformative treatment for estrogen receptor-positive (ER+) and HER2-negative breast cancer.
- Gleevec: Dr. Owen Witte's discovery of the role of tyrosine kinase in chronic myelogenous leukemia paved the way for the development of Gleevec, the first targeted therapy for this disease.
- Keytruda: Dr. Antoni Ribas played a key role in developing and demonstrating the effectiveness of pembrolizumab (Keytruda) for treating advanced melanoma.
- Cyramza: Dr. Edward Garon led a clinical trial that led to the FDA approval of Cyramza for treating lung cancer.
These are just a few examples of the many contributions UCLA researchers have made to the fight against cancer.
A Multidisciplinary Approach
The UCLA Prostate Cancer Program takes a multidisciplinary approach to patient care, bringing together experts from various fields to provide comprehensive and individualized treatment. This team includes urologists, medical oncologists, radiation oncologists, pathologists, radiologists, and clinical trial nurses.
Bi-weekly conferences are held to discuss complex cases and ensure that each patient receives the best possible care.
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