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Focus Feature on Cancer Research News
Finding new ways of understanding the enemy is often key to fighting it
By Jeffrey Bouley
As the Chinese general and philosopher Sun Tzu wrote centuries ago, “If you know the enemy and know yourself, you need not fear the result of a hundred battles.” Honestly, while that sounds nice and has a ring of truth, it’s not always the case, and certainly not in battles with cancer.
It just seems as if the more we know about cancer, the more we find out that we don’t know nearly enough—and maybe that we never will fully understand it. And part of that, of course, is that cancer isn’t just one thing—there are myriad types with multitudes of different characteristics.
Still, though—even if we never seem to know enough and even if every time we peel back a layer we see several more seemingly incomprehensible ones beneath it—the more we know, the better we are able to fight, even if we don’t always win.
To that end, here are several recent stories telling us more about what we know—or need to know—to better advance oncology research and development.
‘Uninhibited’ cells crowd the scene when this pathway goes awry
For all our social nature, people generally don’t like to be packed too tightly. Think crowded buses or subway trains with people trying to maintain their personal space as much as possible even with densely packed spaces. In the same way, noted researchers at Scripps Research in May, cells generally prefer not to be packed in too tightly. In fact, they have set up mechanisms to avoid this, a phenomenon called “contact inhibition.”
As Scripps points out, a hallmark of cancer cells is that they lack this contact inhibition, and instead become “pushy,” facilitating their spread. Unfortunately, scientific understanding of the mechanism underlying this cell behavior change has had many gaps.
That might be on the verge of changing, thanks to a new paper titled “YAP-mediated Recruitment of Q2 YY1 and EZH2 Represses Transcription of Key Cell-Cycle Regulators” from the lab of Dr. Joseph Kissil, a professor of Molecular Medicine at the Florida campus of Scripps Research.
Writing in Cancer Research, a journal of the American Association for Cancer Research, Kissil and colleagues offered new details about how the “stop-growth” signal unfurls during cell-to-cell contact, and how disruption of that stop-growth signal can promote cancer.
A key player is a protein called YAP, a regulator of gene expression. YAP is a major effector of a pathway referred to as the Hippo pathway, so named after geneticists discovered that mutations to the HPO gene produced lumpy, hippo-like tissue overgrowth in fruit fly models.
Healthy cells and developing organs “know” when they should grow and when they should stop growing, based on multiple signaling molecules. These signals are transmitted by YAP and the Hippo pathway. Tracing out those signals is not only central to understanding our basic biology, but to finding new ways to attack cancers with precision therapies, Kissil explains.
Increasing cell density normally activates a change in cell signaling. It does this via an elevation of protein involved in initiating contact inhibition, p27. But a disrupted Hippo pathway interferes with normal YAP behavior and blocks the expected p27 surge.
Kissil and the rest of the team were surprised to find YAP in the uncharacteristic role of shutting down gene transcription. Previous studies suggested that YAP is an activator of genes that promote cell growth. The reality proved to be much more complex.
“What we show here is that YAP can also turn off genes, not just turn them on,” Kissil says. “It shuts down genes that would otherwise prevent cells from proliferating.”
“When we target YAP in cancer, we are targeting its function as an activator of cancer, but we now know we also need to consider its suppressive functions, as well,” Kissil said. “We have to consider both the activation and the repression.”
Finding the players that both interact with YAP and have a functional role in promoting cancer growth required use of a genome-wide bioinformatics technique called ChIP-seq. The team worked specifically in human Schwann cells, which are peripheral nerve cells that produce the insulating myelin around nerves, but the findings should apply to other cancers, Kissil thinks.
The researchers looked at YAP in the context of cell crowding and learned that YAP’s role involves recruitment of other interacting proteins that include YY1 (also known as Yin-Yang 1), EZH2 and a protein complex called PRC2.
Those will also be important to study further, Kissel noted, as well as the interaction of these players in the context of cancer drug resistance.
Is CD40 the key to three-drug combos in immuno-oncology treatments?
Emerging three-drug combinations are poised to redefine the immuno-oncology treatment paradigm in advanced malignancies with high unmet need, according to data and analytics company GlobalData, which adds that the oncology market is “saturated” with new drugs that target the immune system; “however, these only target part of the problem caused by cancer’s ability to hide from the immune system.”
Noted Miguel Ferreira, an oncology and hematology analyst at GlobalData: “To achieve the full potential of this strategy, new targets that independently trigger immune activation in addition to blocking cancer-mediated suppression of the immune system are needed.”
One of the current strategies using checkpoint inhibitors in certain cancer types involves treating with a PD-1 inhibitor, which blocks the ability of the cancer to silence necessary immune cells, and adding a second drug, such as an angiogenesis inhibitor, to help stabilize the response by disrupting the tumor microenvironment.
What is currently missing is a third component, a drug targeting a co-stimulatory T cell receptor which must directly and independently activate T cells to initiate an immune response.
“CD40 has been identified as the leading stimulatory receptor in T-cells that would allow for a three-drug combination strategy by being the agent involved in directly activating the immune response,” said Ferreira. “As a single drug treatment, the dose required to get a sufficient effect might be too high and therefore too toxic, but when used in combination, a lower dose can contribute to the potential synergism between drugs targeting different aspects of the immune system against cancer.”
Protein power vs. tumor growth and damage
Purdue University scientists have created a new therapeutic option that may help halt tumor growth in certain cancers, such as prostate cancer, which is among the most common types of cancer in men. Not only that, but it might fix damage done by tumors during their rampage.
“We have designed a therapy that can help recruit immune cells to kill cancer and also help repair bone and tissues damaged by tumors,” said Dr. Marxa Figueiredo, an associate professor of basic medical sciences in Purdue’s College of Veterinary Medicine, who helped lead the research team and is working with the Purdue Research Foundation Office of Technology Commercialization to patent the innovation. “One of the best features of this technology is that it shows great promise in enabling treatment for many other cancers and diseases that could benefit from halting tumor growth and promoting bone repair.”
The therapy technology is presented in the journal Molecular Therapy: Methods & Clinical Development in a paper titled “Ligand-Mediated Targeting of CytokineInterleukin-27 Enhances Its Bioactivity In Vivo.”
The Purdue team used a protein called interleukin-27, or IL-27, which has shown promise in reducing tumor growth and helping stop cancer from spreading in the body. IL-27 is a cytokine, a kind of protein secreted by cells of the immune system that act as chemical messengers and can help the immune system target cancer and other diseases.
“Immune cells are naturally attracted to areas of the body with lots of signals that come from proteins such as IL-27,” Figueiredo said. “So, with our novel approach of targeting the IL-27 to the tumor or bone cells, we can use these proteins to produce signals that bring healthy cells to areas of the body with cancer or other disease and kill the tumors and begin the process of repairing bone and other musculoskeletal tissues.”
Figueiredo said the new Purdue therapy technology has applications for people and animals with many different types of cancer—including breast and lung—and other diseases where protein targeting could improve the immune system’s response.
A warning of cellular stress; an explanation for chemotherapy resistance
Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk Institute researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on Dec. 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.
“Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, ‘Hey, I’m under attack, you better protect yourself,’” said Dr. Gerald Shadel, a professor in Salk’s Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science.
Most of the DNA that a cell needs to function is found inside the cell’s nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds—or even thousands—of mitochondria.
Shadel’s lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus—by releasing it from mitochondria and launching an immune response that beefs up the cell’s defenses.
In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell’s interior. They homed in on a subset of genes known as interferon-stimulated genes (ISGs), which are typically activated by the presence of viruses. But in this case, the team realized, the genes were a particular subset of ISGs turned on by viruses. And this same subset of ISGs is often found to be activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents like doxyrubicin.
To destroy cancer, doxyrubicin targets the nuclear DNA. But the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage—and, thus, causes increased resistance to the chemotherapy drug. When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells, the cells became more resistant to doxyrubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell’s DNA.
“Perhaps the fact that mitochondrial DNA is present in so many copies in each cell, and has fewer of its own DNA repair pathways, makes it a very effective sensor of DNA stress,” Shadel theorized.
Most of the time, he points out, it’s probably a good thing that the mtDNA is more prone to damage—it acts like a canary in a coal mine to protect healthy cells. But in cancer cells, it means that doxyrubicin—by damaging mtDNA first and setting off molecular alarm bells—can be less effective at damaging the nuclear DNA of cancer cells.
“It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance,” Shadel says. His group is planning future studies on exactly how mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell’s nucleus to ward off damage.
Commentary: CRISPR screening in B cells—A primary tool for target discovery
By Dr. Nicola McCarthy of Horizon Discovery
Gaining a better understanding of how immune cells function, and the factors that affect this, is paramount if we are to fully exploit the immune system’s potential to tackle different diseases. Genetic screens are a valuable tool that enable researchers to identify specific genes responsible for a specific cellular function. Results from genetic screens can be used to find and validate novel biology, drug targets and mechanisms of drug resistance or sensitivity.
CRISPR screening, an application of the CRISPR/Cas9 gene-editing technology that can be used to assess the functions of thousands of genes in a single experiment, can be used for immuno-oncology drug discovery.
The most-used method is CRISPR knockout (CRISPRko), which results in the permanent elimination of gene transcription. Alternative approaches—CRISPR activation (CRISPRa) and CRISPR inhibition (CRISPRi)—either activate or inhibit the transcription of target genes, respectively. Both techniques can be used to produce reversible changes to gene expression with no permanent change to the DNA.1
Such screens can be conducted in either pooled formats (large-to-medium scale screening using a library of guide RNAs expressed in cells grown as a single population) or arrayed formats (small-to-large scale approach using a library of guide RNAs where guides targeting each gene of interest are assessed in individual wells). In cancer cell lines, these approaches can be combined and used to examine the impact of increased or decreased gene transcription on the capacity of immune cells to lyse cancer cells, for example. CRISPR screens are used to investigate drug mechanisms of action, identify biomarkers and provide targets for the development of combination therapies.
CRISPR has been hugely influential in drug development research and has enabled scientists to identify genes relevant to specific biological pathways. Further down the pipeline, CRISPR could help to reduce the risk of clinical trial failures by helping to select compounds with a higher chance of success and stratify patient populations to determine which therapeutics will be most effective.
Physiologically relevant cell models
For decades, screening experiments have been performed using cell lines, as they are stable and predictable, and reliable protocols are well established. Their capacity to divide endlessly in vitro in simple culture media enables researchers to carryout high-throughput screening campaigns to look for new drug targets or drug combinations. However, cells used in this way adapt over time to the culture environment and can develop genetic and morphological changes. This differentiation from the tissues they were originally isolated from means that results cannot always be fully translated into the clinic.
Screens using primary human cells—cells isolated freshly from a human donor—more closely mimic the in-vivo environment they were isolated from. Although culture conditions for primary cells are challenging and each type of cell requires its own specialized media, the use of these cells has the potential to identify more physiologically relevant targets and improve the chances of success in late-stage clinical trials.
The limited expansion capacity of primary cells in vitro is an ever-present challenge to running large-scale gene perturbation screens. Primary T cell screening has been helped by advances in cell therapy research. In CAR-T therapy, researchers have found ways to keep the T cells alive long enough to perform genetic manipulation, expansion and implantation into the patient. Such advances are proving useful to in-vitro screening applications and are being applied by scientists at Horizon Discovery to deliver functional genomic screens in primary human immune cells.
The immune system in cancer
The human immune system can detect tumor cells through a host of different mechanisms, which includes the recognition of tumor specific antigens. However, during the evolution of a tumor, some of these mechanisms start to fail, and this is due in part to cells within the tumor producing cytokines and other suppressive factors that block the expansion of both cytotoxic and helper immune cells.
Immunotherapy drugs, which aim to boost an immune response in patients with cancer, are approved to treat different types of cancer. Checkpoint blockade immunotherapy, which targets surface checkpoint proteins on either the immune cell (PD-1) or the tumor cell (PD-L1), preventing immunosuppressive signals occurring within the immune cells, has proven effective in patients with colorectal, lung and other solid tumors.
Cellular immunotherapies, or adoptive cell therapies, involve extracting immune cells from either the patient (autologous) or another donor (allogeneic), and expanding and modifying these ex vivo before implantation into the patient with cancer. CAR-T therapy, where T cells are genetically modified to express a chimeric antigen receptor (CAR) designed to recognize, bind and destroy cells expressing specific tumor antigens, has shown great promise, especially in the treatment of blood cancers.
With these exciting advances in the use of the immune system to treat patients with cancer, other key players in the immune response are now being investigated for their potential to bolster the immune-based armory.
The importance of B cells to cancer biology
Although B cells are an important contributor to adaptive immunity through antibody production and antigen presentation, research into their role in antitumor activity has been largely overlooked. Instead, research has focused on T cells, owing to their higher concentration in the tumor microenvironment. However, since the discovery of tumor-infiltrating B cells and their ability to differentiate into different B cell subsets in the tumor microenvironment, research efforts have increased substantially.2
B cells have a complex and important role in modulating the immune response to cancer, and whether they inhibit or promote tumor development depends on the type of cancer, and the subtype of B cell. Mechanisms of B cell-mediated tumor suppression revolve around the capacity of B cells to support the function of natural killer (NK) cells and macrophages through antibody production and presenting antigen to T helper and cytotoxic T cells. However, B cells can suppress the antitumor response through the production of antibodies and secretion of pro-tumorigenic factors, including lymphotoxin, a factor that can induce tumor angiogenesis.3,4
One subset of B cells, known as regulatory B cells (Bregs), suppresses the immune response through the production of the cytokine, interleukin-10, and transforming growth factor beta, a suppressor of T-cell immunosurveillance.5 This subset of B cells has recently been used in CRISPR screens, providing a means of understanding more about the biology of these cells.
CRISPR screens in primary human B cells
Using primary B cells isolated from healthy donors, Horizon Discovery developed a CRISPR-mediated gene editing and screening capability in Bregs. As mentioned, Bregs produce IL-10, a cytokine implicated in the onset of autoimmune disorders and in the generation of an immune suppressive tumor microenvironment. Having established a protocol to drive primary human B cell differentiation to Bregs in vitro, we carried out a pilot arrayed CRISPRko screen in these cells to find genetic regulators of IL-10 production, using the production of IL-10 as the end point of the screen. However, the impact of IL-10 in human disease is due to its effect on other cell types. Thus, co-culture assays can also be used as a screening endpoint, in particular looking for genes whose loss in Bregs inhibits their capacity to suppress the proliferation of T cells.
It is anticipated that conducting CRISPR screens in Bregs could identify genes that affect the function of B cells and other immune cell types, and provide insight into the critical role of these cells in cancer and autoimmune diseases, such as lupus, multiple sclerosis and rheumatoid arthritis.
Dr. Nicola McCarthy is manager of the Screening Business Unit at Horizon Discovery.
Treating cancer drug resistance may harm the immune system
JUPITER, Fla.—Sooner or later, most cancer patients develop resistance to the very chemotherapy drugs designed to kill their cancer, forcing oncologists to seek alternatives. Even more problematic, once a patient’s tumor is resistant to one type of chemotherapy, it is much more likely to be resistant to other chemotherapies as well, a conundrum long known as multidrug resistance. Once patients reach this point, the prognosis is often poor, and for the last 35 years scientists have attempted to understand and block multidrug resistance in cancer by using experimental medicines.
A new study from scientists at Scripps Research in Florida raises red flags about this strategy. Inhibiting the key gene involved in cancer drug resistance has unintended side effects on specialized immune system cells called CD8+ cytotoxic T lymphocytes (CTLs), the team found. This could dull anticancer immune responses and potentially increase vulnerability to infection, since CTLs are “killer” T cells, essential in the fight against both viral and bacterial infections and tumors, said lead author Dr. Mark Sundrud, an associate professor of immunology and microbiology at Scripps Research.
Several genes are now recognized for contributing to multidrug resistance in cancer, but the first and most prominent of these is called multidrug resistance-1 (MDR1). Its discovery more than three decades ago set off a race to develop drugs that would inhibit expression of MDR1. But those MDR1 inhibitor drugs have consistently disappointed in clinical trials. The reasons behind these failures have remained enigmatic.
In a new study published in April under the title “Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes” in the Journal of Experimental Medicine, Sundrud and colleagues suggest that the repeated failure of MDR1 inhibitors in human cancer trials may be due to a previously unrecognized—and essential—function of the MDR1 gene in CD8+ cytotoxic T lymphocytes.
Using new genetic approaches to visualize and functionally assess MDR1 expression in mouse cells, the team found that CTLs were unique in their constant and high-level expression of MDR1. In addition, preventing MDR1 expression in CTLs, or blocking its function using inhibitors previously tested in human cancer trials, sets off a chain reaction of CTL dysfunction, ultimately disabling these cells from fighting off viral or bacterial infections.
Considering that these cells are also necessary for warding off most cancerous tumors, blocking MDR1 with existing inhibitors could also cripple natural immune responses to cancers, Sundrud said.
“With the help of our collaborators at New York University Medical Center, we looked at mouse immune cells from five major lymphoid and nonlymphoid tissues: bone marrow, thymus, spleen, lung, and small intestine,” Sundrud said. “It became clear that the types of cells that are key to fighting infections and cancers are among those most sensitive to blocking MDR1 function.”
It has been known for decades that CTLs—as well as “natural killer” cells, a type of white blood cell—express high levels of the MDR1 gene. But because MDR1 has historically been viewed only through the lens of creating multidrug resistance in cancer cells, few researchers thought to ask what MDR1 does during normal immune responses; those that did found confusing and often contradictory results, Sundrud says, likely due to the use of non-specific animal model systems.
Convinced that MDR1 might impact natural immune responses, Sundrud and colleagues sought to devise more specific mouse models to directly visualize and functionally characterize MDR1 expression in vivo. Additional experiments revealed that blocking MDR1 function hampered the earliest stages of the CTL response to infections, when these cells multiply rapidly to reach the numbers needed to kill all viral and bacterial invaders. In line with this result, MDR1 inhibition also affected long-lived immunity to infections that have been previously seen and eradicated. It also affected the cells’ energy organelles, called mitochondria.
“We think that MDR1 plays a special role in helping mitochondria provide energy to growing cells,” Sundrud explained. “So, if you take this away, it makes sense that these cells can’t support the metabolic demand of cell division, and that they ultimately die.”
On one hand, Sundrud said, the research raises questions about the safety and utility of using systemic MDR1 inhibitors as cancer therapies. At the same time, the work reveals important new mechanisms that determine how the immune system fights off infections and develops long-lived memory.
“These insights become all the more pertinent today, given all the questions and concerns related to immunity against the pandemic coronavirus that causes COVID-19,” Sundrud noted. The team is now looking to use this new knowledge to finally nail down a unifying function of MDR1 in all cells, whether it is in CTLs responding to infections, or cancer cells trying to deal with chemotherapeutic agents. In the shorter term, Sundrud and colleagues plan to explore new approaches to redesign existing MDR1 inhibitors to specifically target only cancer cells.
Integrating cancer genetic data into AI
Deep Lens platform aimed at rapidly matching patients to precision therapies and clinical trials
COLUMBUS, Ohio—Deep Lens, a software company focused on a new approach to faster recruitment of the best-suited cancer patients to clinical trials, has integrated proprietary molecular data parsing and management technology into the company’s award-winning clinical trial screening and enrollment platform, VIPER. The company calls this a “breakthrough integration” that will enable cancer care teams, clinical trial sponsors and trial coordinators to immediately and automatically match patients based on the genetic profile of their cancers to the best precision therapies and oncology clinical trials.
The company worked with the University of Miami Office of Technology Transfer to exclusively license the technology. A team from Sylvester Comprehensive Cancer Center (part of the University of Miami Miller School of Medicine) and UHealth Information Technology developed an engine to leverage new ways of consuming and normalizing molecular genetic test results from companies, such as Caris Life Sciences, Foundation Medicine, Guardant Health, NeoGenomics, Tempus and more to automate and expedite the patient screening process.
“Our office facilitates transfer of university innovations for the benefit of the university community and the public,” said Dr. Bin Yan, director of the Office of Technology Transfer. “So, it was a natural fit to work with Deep Lens and integrate our two differentiated technologies to solve a real problem in clinical trial recruitment: limited time and resources for physicians and care teams.”
In the past, the genetic test results were sent to healthcare providers, where a trained specialist or physician would analyze the results for therapy decisions. But, clinical trial coordinators often do not have access to this data or the ability to extract information from it when matching patients to clinical trials, leading to inconsistencies in the screening process and missed opportunities to leverage the data. Now, with integration into the VIPER platform, Deep Lens maintains that molecular test results from any lab vendor, across all patients can be quickly searched and easily analyzed by cancer care teams and clinical trial coordinators immediately and automatically match patients to the best precision-based clinical trials available.
“Deep Lens’ VIPER has already made a big improvement to the patient screening process for our precision trials,” said Jim Langford, vice president of clinical operations at Aivita Biomedical in California. “With the addition of automated molecular-based patient matching, we see VIPER giving us much greater granularity into how we work with our provider sites to drive greater patient engagement.”
The collaboration between Deep Lens and the University of Miami not only provides Deep Lens with additional, differentiated technology in precision medicine but establishes the University of Miami as a collaboration partner for future genomics technology development and project work.
Advanced BioDesign publishes lung cancer data in Oncogene
Study shows for first time benefit of its active compound DIMATE in overcoming drug resistance in NSCLC
LYON, France—Advanced BioDesign, dedicated to developing novel therapies against resistant cancers, today announces promising results using its dual inhibitor DIMATE against an original therapeutic target, the ALDH enzymes family, in pulmonary cancer. The results, recently published in Oncogene, demonstrate that in lung cancer xenografts with high to moderate cisplatin resistance, a combination treatment with DIMATE promotes strong synergistic responses with tumor regression.
In support of these findings, the study highlights a new mechanism of action associated with the therapeutic target: the ALDH enzymes, notably ALDH1A3 and ALDH3A1. High expression of these enzymes confers an aggressive, chemo-resistant behavior in non-small cell lung cancer (NSCLC) and reduces patient survival. This strongly suggests that ALDH1A3 and ALDH3A1 make cancer cells resistant to chemotherapy by disposing of their toxic compounds induced by chemotherapy, such as aldehydes and reactive oxygen species (ROS). A combination of DIMATE together with ROS-inducing agents, such as cisplatin, triggers a potent anti-tumor response at lower doses of chemotherapy, which also results in fewer side-effects.
“This study unravels a new mechanism of action bringing synergy with current chemotherapeutic agents in NSCLC,” said Ismail Ceylan, president of Advanced BioDesign. “Beyond these results, we also demonstrated an important proof of concept using ALDH inhibitors to treat lung cancer. It provides preclinical evidence for their use, singularly or in combination with ROS-inducing chemotherapeutic agents, to kill lung cancer cells more efficiently and overcome patient-specific drug resistance.”
Drug resistance is the main cause of chemotherapy failure in lung cancer. With these findings, Advanced BioDesign will pave the way for a new treatment strategy working synergistically with gold-standard chemotherapies, as most of these have ROS-inducing activities.
Previous studies by Advanced BioDesign research teams also demonstrated the use of DIMATE as a relevant therapeutic option for melanoma and leukemic stem cells. The therapeutic potential of ALDH inhibitors like DIMATE therefore seems to offer broad and promising clinical opportunities in cancer treatment.
“These results, obtained in collaboration with researchers at the University Hospital of Cologne, the University Hospital La Conception in Marseille and others, represent a major step towards a new targeted therapy for the treatment of NSCLC, the most common type of lung cancer. DIMATE is the active compound in Advanced BioDesign’s lead candidate ABD-3001, which is now moving forward into clinical trials as a first-in-class ALDH inhibitor drug for refractory cancers,” said Mileidys Perez, chief scientific officer at Advanced BioDesign.
New diagnostic methods to monitor blood disorders
HERCULES, Calif.—Bio-Rad Laboratories has highlighted its droplet digital PCR (ddPCR) technology in recent months, pointing to research illustrating the sensitivity, precision and speed of Bio-Rad’s ddPCR, which reportedly enables researchers and clinicians to monitor biomarkers of malignant and nonmalignant blood disorders cost-effectively and at scale.
In particular, the company has been focusing on new diagnostics methods, demonstrating how ddPCR is used to monitor patients with hairy cell leukemia (HCL) and chronic myeloid leukemia, particularly in cases when testing must identify low levels of the biomarkers to provide an early indication of whether or not a patient is responding to treatment.
For example, Dr. Pier Luigi Zinzani and Dr. Alessandro Broccoli at the University of Bologna wanted to see if they could find a more sensitive test to determine if patients with HCL are in complete response after cladribine (2CdA) treatment. Using ddPCR, they showed how patients with active disease display a higher fractional abundance of BRAF V600E ctDNA than patients in complete response.
Subsequently, as part of a larger study on 2CdA, Broccoli used ddPCR to test for the presence of this mutation in the peripheral blood of ten patients with HCL who exhibited complete response to 2CdA treatment for at least five years. Seven of these patients were BRAF V6500E-negative. Three patients were positive for the BRAF V600E mutation at 6.5, 8.4, and 13.7 years after treatment, and relapsed between four months and two years later.
Broccoli suggests that these data show how some patients who have long lasting responses after one course of 2CdA will display no evidence of the BRAF V600E mutation in peripheral blood and how ddPCR could potentially be used to monitor the disease activity over time.
“ddPCR is a highly sensitive method, much more sensitive than conventional PCR techniques,” said Broccoli. “This is particularly important for assessing the disease burden in HCL as it is usually characterized by the presence of just a few circulating cells.”