Novel Perspectives on Pancreatic Cancer
Pancreatic cancer continues to be one of the most challenging cancers to diagnose and treat, and, as a result, carries an average survival rate in advanced disease without treatment of just six months after diagnosis and a five-year survival rate that is only in the neighborhood of 10 percent.
The Pancreas Centers of NewYork-Presbyterian are designated as Centers for the Care and Treatment of Pancreatic Cancer by the National Pancreas Foundation. This designation reflects an ongoing commitment to multidisciplinary care that is warranted by the many medical and emotional challenges of caring for patients with pancreatic cancer.
Through their clinical and laboratory investigations, clinicians and researchers at Columbia and Weill Cornell seek to upend the prognosis for this deadly disease. Their endeavors range from basic laboratory studies to uncover barriers to treatment to identifying novel combination therapies in clinical trials that improve survival and are more tolerable in terms of side effects.
At the Forefront of Clinical Trials
A Match Made in the Laboratory
In the Department of Systems Biology at Columbia under the leadership of Andrea Califano, PhD, a research team that spans basic science and clinical departments continues to conduct N-of-1 clinical trials with the goal of identifying existing FDA-approved and investigational compounds that could quickly be tested for effectiveness in blocking master regulators responsible for tumor maintenance.
Building on this concept, recruitment for a new clinical trial – HIPPOCRATES (High-throughput Pancreas Precision Oncology by Cell Regulatory-network Analysis based Therapy Selection) at Columbia will soon be underway for patients with pancreatic cancer. During the clinical trial, tumor tissue removed from patients will undergo whole genome DNA sequencing and RNA expression analysis. Researchers will then analyze this information within the context of models of gene regulation that are specific to that tumor type. This enables them to identify the distinctive master regulators that are required for the cancerous activity in that specific patient’s tumor. Suitable drugs will be immediately tested on the patient’s tumor sample, either in a cell culture or after being implanted into a mouse model, to determine if the compound stops tumor growth. The new trial represents the essence of personalized cancer treatment.
A Triple Threat to Pancreatic Cancer
Researchers at Weill Cornell co-led an international phase 2a clinical trial testing a triple combination of an investigational drug that enables immune cells to infiltrate tumors, an immunotherapy drug, and chemotherapy that has shown promising responses in patients with metastatic pancreatic cancer.
The COMBAT trial, with preliminary data published in the June 2020 issue of Nature Medicine, tested the experimental drug BL-8040, motixafortide, along with the immunotherapy drug pembrolizumab and chemotherapy in 22 patients with metastatic pancreatic cancer whose cancer did not respond to or progressed after a previous, first-line treatment.
The rates of objective response and disease control were 32 percent and 77 percent, respectively. Typical response rates in this patient population with standard chemotherapy alone have been 17 percent and 52 percent, respectively. The median duration of response was 7.8 months. Data collection for overall survival results is ongoing and will be reported when available.
“There is a great unmet need to improve outcomes for this patient population,” says Manuel Hidalgo, MD, Chief of the Division of Hematology and Medical Oncology at NewYork-Presbyterian/Weill Cornell Medical Center and senior member of the Weill Cornell Medicine Meyer Cancer Center in partnership with NewYork-Presbyterian, who led the trial at Beth Israel Deaconness in his previous role as Chief of the Division of Hematology. “Current treatments, including immunotherapies that are transforming outcomes for patients with other solid tumor types, such as lung cancer and melanoma, have had no impact in pancreatic cancer.”
The rationale for the triple regimen in this study is to deliver a 1-2-3 punch to cancer cells. The first involves blocking chemokine receptor-4 (CXCR4), a receptor that is overexpressed on pancreatic cancer cells, drives cancer growth, and has been associated with poor prognoses. The investigational new drug BL-8040 is an engineered small protein that inhibits CXCR4 receptors. The second punch is the immunotherapy pembrolizumab, a checkpoint inhibitor.
Based on additional preclinical data from the manufacturer of BL-8040, the investigators added the standard second-line chemotherapy regimen NAPOLI-1. The chemotherapy helps to increase the efficacy of BL-8040 by making the tumor environment more toxic, and at the same time, decreasing the myeloid-derived suppressor cells (MDSCs), which typically suppress immune responses.
Throughout the study, researchers analyzed blood samples and tumor biopsy samples before and during treatments and observed substantial increases in circulating white blood cells and lymphocytes and T cells infiltrating the tumors, and decreased numbers of MDSCs in the cells in the tumor microenvironment and in the blood. The Weill Cornell researchers are hopeful this triple combination strategy will prove out and merits further investigation in a future phase 3 randomized control trial.
Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM, Golan T, Geva R, Borad MJ, Pedersen KS, Park JO, Ramirez RA, Abad DG, Feliu J, Muñoz A, Ponz-Sarvise M, Peled A, Lustig TM, Bohana-Kashtan O, Shaw SM, Sorani E, Chaney M, Kadosh S, Vainstein Haras A, Von Hoff DD, Hidalgo M. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: The COMBAT trial. Nature Medicine. 2020 Jun;26(6):878-885.
MEKiAUTO: A Three-Pronged Approach to Autophagy and the KRAS Mutation
Evidence from two external independent studies showed that 90 percent of patients with pancreatic cancer have a mutation in KRAS, a gene that activates the MEK pathway. Further studies showed that treatment with a MEK inhibitor in patients who have that activated pathway did not work and, instead, activated the autophagy pathway. “It appeared that the autophagy pathway was serving as a bypass mechanism,” says Gulam Manji, MD, PhD. “The researchers then combined an inhibitor of autophagy with a MEK inhibitor in laboratory studies, and the cancer cells started dying. My thought was that if these cells are dying, they are exposing themselves more to the immune system and, therefore, combining these two drugs with immunotherapy should be an attractive model to test.”
Encouraged by those studies, Dr. Manji developed a proposal for a phase 1 clinical trial – MEKiAUTO – in which patients with KRAS-mutated advanced malignancies would receive a combination therapy with a MEK inhibitor, an immune checkpoint blockade, and an autophagy inhibitor, with the hypothesis that this approach would work by increasing the body’s ability to attack tumors through its immune system.
“The purpose of this study is to determine how safe and effective the combination of atezolizumab, cobimetinib, and hydroxychloroquine is at treating KRAS-mutated advanced malignancies and also determine the maximum dose of this combination of drugs that can be tolerated by patients,” says Dr. Manji. “We believe the combination of the two drugs with immunotherapy could be a successful strategy. This clinical trial is currently ongoing here at Columbia and is the only clinical trial that I’m aware of that is combining the two drugs or any of the two pathways in combination with immunotherapy.”
Metabolism Therapy: Less Toxicity, Longer Survival
Clinicians at Weill Cornell, led by medical oncologist Allyson J. Ocean, MD, are enrolling patients in a phase 3 multicenter clinical trial evaluating SM-88 as a novel cancer metabolism-based therapy for patients with advanced pancreatic ductal adenocarcinoma. “The oral modified dysfunctional tyrosine SM-88 has a novel mechanism of action that allows for it to provide encouraging survival benefit in patients with advanced pancreatic cancer without increased toxicity,” notes Dr. Ocean in an interview with OncLive. “We really don’t have a non-toxic treatment for this disease and getting a drug that improves overall survival in the third-line setting to more than 2.5 months, is a win. The fact that this potential therapy would not have many adverse effects is also a win.”
According to Dr. Ocean, SM-88 enters the cell and disrupts protein synthesis. “The agent also has functions that act as a way to increase oxidative stress within the cell, meaning there is more formation of reactive oxygen species, which then kill the cancer cell,” explains Dr. Ocean. “We’ve also seen data demonstrating that SM-88 can reduce endoplasmic reticulum stress…and if we reduce it with medicines, then we can more effectively kill the cancer cell.”
SM-88 also inhibits autophagy, the process in which cancer cells recycle their own components to help maintain their growth. “Essentially, the agent serves as dysfunctional tyrosine amino acid that gets into the cell and tricks the cell that it's giving it an essential amino acid that it needs to grow and multiply,” continues Dr. Ocean. “However, this dysfunctional amino acid, tyrosine, cannot sustain the growth of cells and actually interrupts protein synthesis and instead starves the cell.”
The phase 3 study builds on results of a phase 2 study with SM-88 conducted in patients with pancreatic cancer who had already undergone two prior lines of chemotherapy. The median overall survival in the patients who took SM-88 was 6.4 months, significantly better than the 2.5-month survival that is usually seen. The agent, which has a favorable toxicity profile, is considered beneficial in terms of maintaining stable disease and the hope is that this will translate into improved overall survival.
“We are now looking at SM-88 in the second-line setting and in patients with earlier stage disease through the Precision Promise clinical trials framework of which Weill Cornell is a member and in collaboration with the Pancreatic Cancer Action Network,” says Dr. Ocean.
Can Managing Stress Promote Survival in Pancreatic Cancer?
Two years ago, an experimental study by Columbia researchers in mouse models demonstrated that stress accelerates the development of pancreatic cancer by triggering the release of catecholamines – the fight-or-flight hormones. The catecholamines within the pancreas drive production of molecules that stimulate nerve growth around tumors. Those new nerves, in turn, promote tumor development and make more catecholamines, perpetuating the cycle.
Beta blockers, commonly used medications that inhibit these hormones, were found to increase survival in a mouse model of the disease.
In experiments with a different mouse model of pancreatic cancer, the research team demonstrated that treating mice with chemotherapy and beta-blockers lived significantly longer than mice treated with chemotherapy alone. An additional analysis of patients with advanced pancreatic cancer revealed that those who were taking beta-blockers for another condition lived approximately two-thirds longer than those who were not taking the medications.
The researchers have now initiated a proof-of-concept clinical trial to determine if giving beta-blockers to patients for a week before surgery has an effect on the tumor. If they can demonstrate that the pathway is affected the way that it is expected to be, a larger clinical trial will be developed with the goal of potentially including beta-blockers as a component of the overall treatment regimen for pancreatic cancer.
Renz BW, Takahashi R, Tanaka T, Macchini M, Hayakawa Y, Dantes Z, Maurer HC, Chen X, Jiang Z, Westphalen CB, Ilmer M, Valenti G, Mohanta SK, Habenicht AJR, Middelhoff M, Chu T, Nagar K, Tailor Y, Casadei R, Di Marco M, Kleespies A, Friedman RA, Remotti H, Reichert M, Worthley DL, Neumann J, Werner J, Iuga AC, Olive KP, Wang TC. β2 Adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell. 2018 Jan 8;33(1):75-90.e7.
Breaking Ground in Pre-Clinical Trials
Boosting Chemotherapy Effectiveness
According to new preclinical research by Weill Cornell Medicine and NewYork-Presbyterian investigators, the targeted drug palbociclib may boost the effectiveness of chemotherapy in pancreatic cancer if the two treatments are given in the right sequence. The study, published in October 2020 in Cancer Cell, found that palbociclib may stop pancreatic cancer cells from repairing DNA damage caused by chemotherapy, and that damage is what causes the cancer cells to die. This result suggests that chemotherapy drugs used for pancreatic cancer, such as paclitaxel, should be given first, with palbociclib being administered afterward.
According to the researchers, the goal is to be able to administer less chemotherapy and to make the chemotherapy for pancreatic cancer more effective. Scientists have been interested in the potential of cyclin-dependent kinase (CDK) inhibitors, such as pablociclib, which are already approved for metastatic breast cancer, to improve outcomes in pancreatic cancer treatment. These drugs block the enzymes CDK 4 and 6, which are important for cell division, a hallmark of tumor malignancy.
Scientists initially found that using CDK 4/6 inhibitors at the same time as chemotherapy made pancreatic tumors more resistant to chemotherapy. The inhibitors prevented cancer cells from entering a phase of the cell cycle in which DNA replicates and becomes vulnerable to damage from chemotherapy drugs.
In the new study, researchers found that the sequence in which these drugs are given is critical. They studied the activity of the chemotherapy drug paclitaxel and palbociclib in mice with human pancreatic tumors and in mice with genetic mutations found in pancreatic cancer. They discovered that giving paclitaxel first and palbociclib second reduced pancreatic cancer cell growth. In contrast, giving the mice palbociclib first and paclitaxel second caused the chemotherapy to destroy fewer cancer cells.
The Weill Cornell researchers found that giving palbociclib after chemotherapy essentially gave tumors a one-two punch. Oftentimes, with chemotherapy some cancer cells die but other cancer cells find a way to recover. Palbociclib prevents the recovery process by interfering with several DNA repair mechanisms, one of which is dependent on the protein Poly (ADP-ribose) polymerase (PARP). Because several PARP inhibitors are already FDA-approved for breast, ovarian, and prostate cancers with BRCA mutations, the Weill Cornell team wants to study them along with chemotherapy and CDK 4/6 inhibitors in pancreatic cancer.
The researchers plan to investigate the mechanisms of action and interaction, the timing and sequence of giving these drugs, and then conduct clinical trials with a goal to put pancreatic cancer cells in a state where they cannot repair damage at all, so that the cells die and patients achieve better outcomes.
Salvador-Barbero B, Alvarez-Fernández M, Zapatero-Solana E, El Bakkali A, Menéndez MDC, López-Casas PP, Di Domenico T, Xie T, VanArsdale T, Shields DJ, Hidalgo M, Malumbres M. CDK4/6 inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma. Cancer Cell. 2020 Oct 12;38(4):584.
Identifying Targets with Encouraging Potential
A study by Columbia researchers published in the April 3, 2020 issue of Science suggests a compound in development for a rare kidney stone disease may have potential against pancreatic cancer. The compound starves tumors of an amino acid, cysteine, which was found to be critical to the survival of pancreatic cancer cells.
All cells, including pancreatic tumor cells, use cysteine to manufacture molecules that detoxify oxidants. Most pancreatic tumors ramp up the production of oxidants and thrive under these toxic conditions by importing large amounts of cysteine into their cells.
“Since pancreatic tumors appear to depend on cysteine import for their survival, we hypothesized that it might be possible to slow tumor growth by selectively targeting this amino acid,” says Kenneth P. Olive, PhD, Director, Oncology Precision Therapeutics and Imaging Core Shared Resource at Columbia and senior author of the study. “We found that when the gene that controls cysteine import was knocked out in mice with pancreatic cancer closely resembling human tumors, cutting off the cancer’s supply of cysteine, the tumors stopped growing and median survival time doubled. Importantly, cysteine depletion did not appear to harm healthy, normal cells.”
The researchers achieved similar results when the mice were treated with cysteinase – an experimental drug that breaks down cysteine in the blood that is under development by researchers at the University of Texas Southwestern Medical Center for the treatment of cystinuria. Human pancreatic cancer cells also appear to be dependent on cysteine, the researchers found. When cysteinase was added to human pancreatic cancer cells in tissue culture, cancer cells died. The Columbia researchers are now planning to test whether combining cysteinase with other treatments, including immunotherapy, can magnify its effect.
Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V, Sagalovskiy IR, Ma A, Kapilian J, Firl CEM, Decker AR, Sastra SA, Palermo CF, Andrade LR, Sajjakulnukit P, Zhang L, Tolstyka ZP, Hirschhorn T, Lamb C, Liu T, Gu W, Seeley ES, Stone E, Georgiou G, Manor U, Iuga A, Wahl GM, Stockwell BR, Lyssiotis CA, Olive KP. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science. 2020 Apr 3;368(6486):85-89.
Organoid Models: A Compelling Competitor to Mouse-Based Research
Researchers from Weill Cornell Medicine, Harvard Medical School, and other institutions have provided evidence that patient-derived organoid models rival the more expensive and time-consuming mouse-based models for pancreatic cancer research. The mouse-based models that are considered the gold standard for preclinical research on pancreatic cancer use patient-derived (PDX) tumors that have been transplanted into mice that lack a functional immune system.
In a study published online Sept. 29 in JCI Insights, the researchers grew organoids from PDX tumors and compared the utility of the organoids to PDX mouse tumors as pancreatic cancer models, finding that the responses of the organoids to standard cancer treatments were as informative as those of the PDX mouse tumors for predicting whether the patient would benefit from the treatment. They further demonstrated that the organoids retain a key molecular feature of pancreatic tumors and PDX tumors: a rearrangement of glycans on the tumor cells, a suspected contributor to the development and progression of these cancers.
The investigators also used the pancreatic tumor organoids to identify several proteins that are highly expressed in these tumors but not in healthy pancreatic cells. They found that the majority of these proteins also are highly expressed in blood samples from patients, and thus may be able to serve as early-warning biomarkers of pancreatic cancer. According to the authors, the results provide a roadmap for using organoids to study pancreatic cancer biology and for rapidly and effectively identifying biomarkers that can be translated to the clinic.
Huang L, Bockorny B, Paul I, Akshinthala D, Frappart PO, Gandarilla O, Bose A, Sanchez-Gonzalez V, Rouse EE, Lehoux SD, Pandell N, Lim CM, Clohessy JG, Grossman J, Gonzalez R, Del Pino SP, Daaboul G, Sawhney MS, Freedman SD, Kleger A, Cummings RD, Emili A, Muthuswamy LB, Hidalgo M, Muthuswamy SK. PDX-derived organoids model in vivo drug response and secrete biomarkers. JCI Insight. 2020 Nov 5;5(21):e135544.
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