Androgen receptor (AR) signaling affects response to BRAF/MEK inhibitor therapy in both males and females with melanoma, researchers from The University of Texas MD Anderson Cancer Center showed in a study published today in Nature. The findings provide a new target to combat therapeutic resistance and one possible answer to why men face a poorer prognosis than women when diagnosed with melanoma.
The AR is a type of nuclear receptor that’s activated by the male sex hormone testosterone. Females have lower levels of androgens, including testosterone. This research confirms the impact of biological sex on response to BRAF/MEK targeted therapy and shows for the first time that these inhibitors increase AR signaling, leading to therapeutic resistance and poor response to treatment. In preclinical models of melanoma, blocking the AR improved response to BRAF/MEK targeted therapy in both males and females.
“This study, coupled with other recent publications looking at the impact of AR signaling on response to other types of cancer therapies, such as immune checkpoint blockade, has enormous implications for the field,” said senior corresponding author Jennifer Wargo, M.D., professor of Genomic Medicine and Surgical Oncology. “We know males and females get cancer at different rates and have different mortality. Our research raises the possibility that the AR and testosterone may be at play and offers a new target to improve response to treatment in both sexes.”
Biological sex matters for targeted therapy response in melanoma
The study began with an observation from a neoadjuvant clinical trial for BRAF/MEK inhibitors in stage III melanoma (NCT02231775) where female patients had a higher rate of major pathologic response (MPR, defined as <10% viable tumor at time of surgery) rates and recurrence-free survival (RFS) rates than male patients.
To validate these findings, the group studied additional patients with locally advanced metastatic melanoma, including 51 patients treated with neoadjuvant BRAF/MEK inhibitors (30 females and 21 males). The MPR rate was 66% for females and 14% for males, and the two-year RFS rate was 64% for females and 32% for males.
After ruling out other possible factors contributing to MPR — including age, performance status, body mass index (BMI), stage of disease and mutation status — the research team validated the sexual dimorphism in several other cohorts. The analysis included a total of 664 patients who received BRAF- and/or MEK-targeted therapy for stage III or stage IV melanoma. In multiple studies, the researchers found a trend toward improved progression-free survival (PFS) and overall survival (OS) in females versus males.
Longitudinal evaluation of available tissue samples revealed significantly higher levels of AR in male patients during treatment compared to baseline, and significantly higher levels of AR during treatment in male and female patients whose cancer did not respond to the targeted therapy combination.
Role of AR signaling validated in preclinical studies
In collaboration with MD Anderson’s Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, the researchers validated their observational findings in several preclinical models.
“This study speaks to our commitment to transform patient care through a reverse translation strategy that is exemplified at MD Anderson,” said co-corresponding author Timothy Heffernan, Ph.D., vice president of oncology research in MD Anderson’s Therapeutics Discovery division and head of TRACTION.
First, they showed that female mice implanted with melanoma tumors respond better than male mice to BRAF/MEK inhibitor therapy. When all mice were given testosterone, tumor progression and treatment resistance occurred in both sexes. Finally, when mice were given an AR inhibitor plus targeted therapy, responses to melanoma treatment improved in both sexes.
“By using translational studies in patient samples alongside preclinical models, we showed that treatment with BRAF/MEK inhibitors is associated with upregulation of the AR on tumor cells, thus promoting resistance to therapy,” said co-corresponding author Joseph Marszalek, Ph.D., co-leader of TRACTION. “We found that blocking the AR actually improved treatment response in males and females, and that activating AR signaling with testosterone abrogated therapeutic response.”
Recent research showed that AR-mediated resistance may have an impact on other cancers and types of treatment. The current findings emphasize the need to better understand the impact of receiving hormone therapy while undergoing BRAF and/or MEK inhibitor therapy for melanoma and other cancers.
“There are many factors that can influence differences between biological sex and cancer outcomes, but hormones will be one of the next big areas of research focus,” Wargo said. “The good news is that we already have ways to modulate hormones, so the field is well-positioned to develop studies and novel therapeutics to take into the clinic. There are brilliant investigators at MD Anderson and worldwide who already are studying the use of AR blockade in combination with other cancer treatments across several cancer types.”
The study was supported by the Melanoma Moon Shot®, part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives, as well as the Cancer Prevention and Research Institute of Texas (RP170002).
Wargo has served as a consultant/advisory board member for and receives research support from GlaxoSmithKline and Novartis. A full list of co-authors and disclosures is available in the paper.
The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. Current advances include new biomarkers to predict chimeric antigen receptor (CAR) T cell therapy outcomes and neurotoxicities, novel treatment targets for pre-cancerous pancreatic lesions and T-cell acute lymphoblastic leukemia, a new approach to improve immunotherapy responses in cold tumors, a profile of synthetic lethal targets for cancers with tumor suppressor loss, and promising clinical data for acute myeloid leukemia and cancers of unknown primary.
Pre-treatment DNA copy-number changes predict CAR T cell therapy
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 can achieve long-term remissions in many patients with advanced large B-cell lymphoma, but more than half will not benefit from this approach. Predictive biomarkers are needed to identify those not likely to respond so that physicians can consider additional or alternative treatments. In a new study led by Hua-Jay (Jeff) Cherng, M.D., Michael Green, Ph.D., and Jason Westin, M.D., researchers discovered that genetic copy-number alterations (CNAs) evident in pre-treatment blood samples were predictive of inferior response rates to CD19 CAR T cell therapy. The team performed low-pass whole genome sequencing on cell-free DNA isolated from the blood of 122 patients before treatment. A high CNA score, denoting genomic instability, was associated with significantly lower complete response rates, progression-free survival and overall survival when compared to patients with a low CNA score. By combining this score with traditional markers of tumor bulk, the researchers built a risk model to reliably predict patient outcomes. Learn more in Blood.
PPARδ signaling accelerates cancer progression in
KRAS-mutant pancreatic lesions
Pancreatic intraepithelial neoplasia (PanIN) are lesions within the pancreas that can develop into pancreatic cancer. Most PanIN lesions have mutations in the KRAS gene that can drive cancer development, but relatively few lesions actually progress to cancer. Understanding factors that promote progression is critical to developing intervention strategies. Researchers led by Yi Liu, Ph.D., Xiangsheng Zuo, M.D., Ph.D., and Imad Shureiqi, M.D., discovered that activated PPARδ — a hormone receptor found in the cell nucleus — accelerates progression of KRAS-mutant PanIN lesions. The researchers demonstrated that PPARδ expression is elevated in PanIN lesions through the activity of mutant KRAS. When activated by a synthetic ligand called cardarine (GW501516) or a high-fat diet, PPARδ stimulates pancreatic epithelial cells to secrete the CCL2 chemokine, which recruits suppressive immune cells into the tumor microenvironment. Blocking signaling downstream of CCL2 suppressed pancreatic cancer development driven by PPARδ. The findings suggest that targeting the PPARδ pathway may be a viable strategy to prevent PanINs from progressing to pancreatic cancer. Learn more in Nature Communications.
Targeting oxidative phosphorylation may be effective in
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia often driven by NOTCH1 mutations. Unfortunately, targeting NOTCH1 has proven challenging, so alternative therapeutic approaches for these cancers are needed. Researchers led by Natalia Baran, M.D., Ph.D., and Marina Konopleva, M.D., Ph.D., demonstrated that the oxidative phosphorylation (OxPhos) metabolic pathway is critical for survival and chemotherapy resistance in NOTCH1-mutant leukemia cells. Mutant NOTCH1 led to activation of the OxPhos pathway, and targeting OxPhos with IACS-10759 — a small-molecule inhibitor developed by MD Anderson’s Therapeutics Discovery division — blocked proliferation in NOTCH1-mutant cells. Blocking OxPhos led to metabolic reprogramming that increased dependency on glutamine metabolism. Combining IACS-10759 with the chemotherapy asparaginase or with glutaminase inhibitors, both of which disrupt glutamine metabolism, leveraged this vulnerability and led to profound tumor reductions in preclinical T-ALL models. The findings suggest this strategy warrants further study as a new treatment approach. Learn more in Nature Communications.
Preclinical study turns “cold” tumors “hot” through LFA-1 activation
Immune checkpoint blockade targeting PD-1 and CTLA-4 has transformed cancer treatment, particularly in melanoma, but not all patients benefit from immunotherapy. Multiple studies have identified a “cold” tumor microenvironment (TME), with few T cells, as one reason immunotherapy is not successful against some cancers. Lymphocyte function–associated antigen-1 (LFA-1) is known to recruit T cells to the TME. A preclinical study led by Yared Hailemichael, Ph.D., used 7HP349, a small molecule activator of LFA-1, alone and in combination with anti-CTLA-4 therapy in a non-T cell inflamed tumor model. While 7HP349 monotherapy had a modest effect, T cells were enriched in the TME when combining 7HP349 with anti-CTLA-4 therapy. This proof-of-concept study lays the groundwork for further research on LFA-1 activation to improve response to immune checkpoint blockade. Learn more in JCI.
Genomic screen finds potential treatment targets for cancers with
tumor suppressor loss
Tumor suppressors normally work to block cancer growth, but when they are lost or inactivated by mutation, abnormal cells can grow unchecked. Unfortunately, this loss of function means that tumor suppressors cannot be targeted directly. One alternative strategy is to take advantage of synthetic lethality, in which cancer cells with tumor suppressor loss become hypersensitive to drugs targeting related pathways. To identify potential synthetic lethal targets, a research team led by Junjie Chen, Ph.D., and Traver Hart, Ph.D., performed a genome-wide screen in 12 engineered cell lines, each with a common tumor suppressor knocked out. Using CRISPR/Cas9 gene editing, the researchers systematically inactivated more than 18,000 genes in each cell line and identified more than 300 genes that may be potential synthetic lethal targets for at least one tumor suppressor. Interestingly, they discovered that targeting one tumor suppressor may be a viable therapeutic strategy for cancers with loss of another tumor suppressor. This study provides a useful resource for researchers to identify novel therapeutic strategies for cancers with tumor suppressor loss. Learn more in Science Advances.
New study offers potential treatment for cancer of unknown primary
Cancer of unknown primary (CUP) is an aggressive rare disease in which the cancer has metastasized to other parts of the body, but the origin of cancer growth cannot be determined. Because the primary site is unknown, this type of cancer is difficult to treat with limited therapeutic options. In a Phase II basket trial for independent rare tumor cohorts, including CUP, Aung Naing, M.D., and a team of MD Anderson researchers evaluated the safety and efficacy of pembrolizumab in 29 patients with advanced CUP. Of the 25 evaluable patients, seven (28%) achieved non-progression at 27 weeks. In addition, the drug achieved an overall response rate of 20%, with immune-related partial response in five patients and a median duration of response of 14.7 months. Treatment-related adverse events of any kind were observed in 19 patients (76%) and grade ≥3 in four patients (16%), respectively. One patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Overall, pembrolizumab was well-tolerated and demonstrated encouraging efficacy in patients with CUP. Learn more in the Journal for ImmunoTherapy of Cancer.
Combination induction therapy for AML shows favorable responses and
Most younger patients with acute myeloid leukemia (AML) respond favorably to initial chemotherapy, but many will experience a subsequent relapse. Once disease relapse occurs, outcomes are poor and new therapies are needed. An expanded study, led by Courtney DiNardo, M.D., Hagop Kantarjian, M.D., and Curtis Lachowiez, M.D., found that an intensive regimen of fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-IDA) combined with venetoclax produced deep remissions that correlated with durable survival. The overall response rate was 98% and minimal residual disease (MRD)-negative complete response rates exceeded 90%. Median event-free survival (EFS) and overall survival (OS) were not reached but were estimated at 24 months to be 64% and 76%, respectively. In patients attaining MRD-negative responses, estimated EFS and OS were 75% and 82%. The combination therapy helped bridge patients to successful stem cell transplants. The study continues to enroll patients with newly diagnosed and relapsed or refractory AML at MD Anderson. Learn more in the American Journal of Hematology.
Clonal hematopoiesis linked to severe neurotoxicity following CAR T
Durable responses are achieved in many patients with hematologic cancers treated with chimeric antigen receptor (CAR) T cell therapy, but the treatments can cause significant neurological toxicities. Despite progress, many of the underlying causes of these toxicities remain unknown. Clonal hematopoiesis (CH) — the expansion of hematopoietic stem cells with somatic mutations — can drive systemic inflammation, but its connection to these neurotoxicities was not understood. In a new study, Neeraj Saini, M.D., Sattva Neelapu, M.D., and Koichi Takahashi, M.D., Ph.D., and colleagues discovered that CH mutations, particularly those with epigenetic machineries, are linked with severe-grade neurotoxicities in lymphoma patients treated with CD19 CAR T cell therapy. Through targeted DNA sequencing, they detected CH mutations in 36.8% of pre-treatment samples from 114 patients. Grade 3 or higher neurotoxicities were observed in 45.2% of patients with CH, compared to just 25% of those without CH. Future studies will aim to understand how CH may drive neurotoxicity and to develop novel intervention strategies to prevent or treat these conditions. Learn more in Blood Cancer Discovery.
In case you missed it
Read below to catch up on recent MD Anderson press releases.
The University of Texas MD Anderson Cancer Center and National Resilience, Inc., today announced the launch of a joint venture, the Cell Therapy Manufacturing Center (CTMC), to accelerate the development and manufacturing of innovative cell therapies for patients with cancer. Uniting the strengths of Resilience and MD Anderson, the joint venture will advance its work within a culture of academic innovation alongside industrial expertise.
CTMC will be based in a state-of-the art 60,000-square-foot manufacturing facility in the Texas Medical Center, with a team of 70 employees focused on process and analytical development as well as early-phase and clinical-stage Good Manufacturing Practices (GMP).
The joint venture combines MD Anderson’s expertise in immunotherapy and cell therapies as well as a leading clinical trials infrastructure, with Resilience’s innovative biomanufacturing technologies, advanced analytics, and a national network for developing and producing cell therapies. Together, the parties aim to accelerate the path of cell therapies to the clinic, while enabling scalability and a smooth transition to late-phase clinical and commercial activities.
“Cell therapies have had a dramatic impact for patients with certain cancers, but progress has been hampered by structural challenges,” said Jason Bock, Ph.D., chief executive officer of CTMC. “This novel joint venture was conceived to address those challenges by harnessing the complementary capabilities of two world-class organizations, allowing us to advance innovative programs to deliver impactful therapies to patients.”
The joint venture will engage with MD Anderson researchers and external industry collaborators to advance new therapies through preclinical and clinical development, ensuring consistent and safe products that can be evaluated rapidly in clinical trials led by MD Anderson physicians. Resilience customers will be able to leverage this offering as part of the company’s growing network of biomanufacturing facilities that are flexible enough to scale projects from small-batch pre-clinical to large-scale commercial production. Resilience has 10 facilities across North America, with more than one million square feet of manufacturing space.
“The promise of cell therapies to help patients in need has been limited by a lack of innovation in biomanufacturing,” said Rahul Singhvi, Sc.D., chief executive officer of Resilience. “This collaboration aims to overcome those hurdles by extending our network with this unique partnership, creating opportunities to incubate innovative ideas and provide cutting-edge biomanufacturing technologies and processes to researchers, with a goal of bringing more cell therapies to patients.”
The joint venture will advance the most promising cell therapy modalities to answer unmet clinical needs, including engineered tumor infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR)-modified T cells, endogenous T-cells (ETCs), engineered natural killer (NK) cells and other emerging technologies, for patients with hematological and solid tumors. MD Anderson researchers are leaders in the field of cancer cell therapy, responsible for advancing the translational and clinical development of many of the currently approved and experimental cell therapies.
The joint venture is built upon MD Anderson’s Biologics Development platform, formerly part of the institution’s Therapeutics Discovery division. Current strategic collaborations with MD Anderson’s Biologics Development platform will continue; collaborative relationships with MD Anderson’s Therapeutics Discovery division, as well as physicians and scientists across the institution, also will be maintained.
“We believe in the tremendous potential of cell therapies to deliver solutions that offer cures, not merely prolonged survival. Resilience offers unique capabilities that make it an ideal choice for unlocking that potential and accelerating impactful cell therapies,” said Ferran Prat, Ph.D., J.D., senior vice president for Research Administration and Industry Relations at MD Anderson. “Our mission at MD Anderson is to end cancer, and this joint venture is a strategic step toward realizing that goal.”
MD Anderson has an institutional conflict of interest with National Resilience, Inc. and CTMC, and these relationships will be managed according to an MD Anderson Institutional Conflict of Interest Management and Monitoring Plan.
A multicenter research team co-led by The University of Texas MD Anderson Cancer Center developed the first drug to treat the uncontrolled secretion of mucins in the airways, which causes potentially life-threatening symptoms in millions of Americans with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), as well as lung disease resulting from cancer and cancer treatment. The study was published today in Nature.
“Mucus is a significant problem in pulmonary medicine, because in people with these common lung diseases, thick mucus can block the airways and cause symptoms ranging from a mild cough to very serious decreases in lung function,” said Burton Dickey, M.D., professor of Pulmonary Medicine and co-corresponding author of the study. “Most drugs for these conditions work to reduce inflammation or expand the airways to help people breathe better, but mucus is the most serious issue. Our research has created the first drug that would stop the secretion of mucins in its tracks.”
Muco-obstructive lung diseases affect hundreds of millions of people worldwide. In the U.S., about 25 million people have asthma, 16 million adults have been diagnosed with COPD and CF is the most common life-threatening, genetic disease. Many cancer patients end up with lung disease because their cancer treatments or the cancer itself leaves them immunocompromised.
Normally, mucins are gradually released into the airways, where they absorb water and form a thin layer of protective mucus that traps pathogens and is easily cleared by cilia. In muco-obstructive lung diseases, high volumes of mucins are suddenly released and, unable to absorb enough water, result in a thick mucus that can plug airways and impair lung function.
Dickey’s lab began studying mucin secretion two decades ago and previously identified the key genes and proteins involved, showing how synaptotagmin and a SNARE complex, similar to that found in neurons, contribute to the key process of Ca2+-triggered membrane fusion.
“We built up a picture of what the secretory machinery looked like and we knew all of the major players,” Dickey said. “Once we had an idea of how all the pieces worked together, we determined synaptotagmin-2 (Syt2) was the best protein to target to block mucin secretion because it only becomes activated with a high level of stimulation. Therefore, blocking the activity of Syt2 should prevent sudden massive mucin release without impairing slow, steady baseline mucin secretion that is required for airway health.”
In this study, a collaborative effort between MD Anderson, Stanford Medicine and Ulm University, the researchers verified Syt2 as a viable therapeutic target protein in several types of preclinical models. Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of the Institute for Applied Cancer Science, designed a hydrocarbon-stapled peptide, SP9, to block Syt2, based on structures developed by the Stanford collaborators, including senior co-corresponding author Axel Brunger, Ph.D., professor of Molecular and Cellular Physiology.
Stapled peptides are a recent therapeutic development involving modified amino acids that form hydrocarbon crossbridges to hold their structure rigid so they can bind to a protein target and show enhanced stability. Stapled peptides have been used to treat other diseases, including cancer, but SP9 would represent the first stapled peptide to be used as an inhaled therapeutic.
In a reconstituted system model in Brunger’s Stanford laboratory,
Ying Lai, Ph.D., used SP9 to successfully disrupt
Ca2+-triggered membrane fusion. The Ulm laboratory of Manfred Frick,
Ph.D., used SP9 conjugated to a cell penetrating peptide in cultured
epithelial cells to inhibit rapid mucin secretion. The Dickey
laboratory then used an aerosolized version in a mouse model to
confirm the drug reduced mucin secretion and airway blockage by mucus.
Importantly, SP9 did not affect the slow-release pathway for normal
“An inhaled drug like this could help someone during an acute attack of airway disease by stopping the rapid secretion of mucin and, by extension, avoiding production of thick mucus. You can’t move air through an airway that’s plugged,” Dickey said. “In asthma, COPD and CF, it’s been shown that persistent plugs drive the most serious disease. Now we have a drug that could be very important if it’s shown to work in clinical trials.”
The stapled peptide SP9 will be further refined before moving to human studies, as is typical for therapeutics at this stage of development, and may enter clinical trials in a couple of years.
Dickey and co-authors are inventors on a patent application related to SP9. The study was supported by the National Institutes of Health (R01 HL129795, R21 AI137319) and the Cystic Fibrosis Foundation. A full list of co-authors and their disclosures is available in the paper.