Aleksander S Popel

• Ph.D.
• Professor at Johns Hopkins University

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and a major cause of cancer-related deaths worldwide. HCC is characterized by low survival rates and a high incidence of recurrence. Systemic therapy responses are observed in only a small proportion of HCC patients. Our spatial transcriptomics (ST) analysis of HCC tumors fro...

The bigger picture Breast cancer is one of the most common cancers in women and, unfortunately, telling how or when a patient will respond to a given treatment continues to be poorly understood——particularly in the cases of most aggressive breast cancer subtypes. The complex biology reflected in the tissue surrounding and including the tumor, known...

Despite an increasing number of clinical trials, cancer is one of the leading causes of death worldwide in the past decade. Among all complex diseases, clinical trials in oncology have among the lowest success rates, in part due to the high intra- and inter-tumoral heterogeneity. There are more than a thousand cancer drugs and treatment combination...

Patients with metastatic triple-negative breast cancer (TNBC) show variable responses to PD-1 inhibition. Efficient patient selection by predictive biomarkers would be desirable but is hindered by the limited performance of existing biomarkers. Here, we leveraged in silico patient cohorts generated using a quantitative systems pharmacology model of...

Uveal melanoma (UM), the primary intraocular tumor in adults, arises from eye melanocytes and poses a significant threat to vision and health. Despite its rarity, UM is concerning due to its high potential for liver metastasis, resulting in a median survival of about a year after detection. Unlike cutaneous melanoma, UM responds poorly to immune ch...

Advancements in imaging technologies have revolutionized our ability to deeply profile pathological tissue architectures, generating large volumes of imaging data with unparalleled spatial resolution. This type of data collection, namely, spatial proteomics, offers invaluable insights into various human diseases. Simultaneously, computational algor...

Computational methods that simulate tumors mathematically to describe cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirely in silico, potentially greatly accelerating the delivery of new therapeutics to patients. To facilitate the design of dosing regimens and identification of potential bio...

Recently, immunotherapies for antitumoral response have adopted conditionally activated molecules with the objective of reducing systemic toxicity. Amongst these are conditionally activated antibodies, such as PROBODY® activatable therapeutics (Pb-Tx), engineered to be proteolytically activated by proteases found locally in the tumor microenvironme...

Immune checkpoint inhibitors remained the standard‐of‐care treatment for advanced non‐small cell lung cancer (NSCLC) for the past decade. In unselected patients, anti‐PD‐(L)1 monotherapy achieved an overall response rate of about 20%. In this analysis, we developed a pharmacokinetic and pharmacodynamic module for our previously calibrated quantitat...

Patients with metastatic triple-negative breast cancer (TNBC) show variable responses to PD-1 inhibition. Efficient patient selection by predictive biomarkers would be desirable, but is hindered by the limited performance of existing biomarkers. Here, we leveraged in-silico patient cohorts generated using a quantitative systems pharmacology model o...

The tumor microenvironment is widely recognized for its central role in driving cancer progression and influencing prognostic outcomes. Despite extensive research efforts dedicated to characterizing this complex and heterogeneous environment, considerable challenges persist. In this study, we introduce a data-driven approach for identifying pattern...

Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic peptide derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only as an anti-angiogenic peptide but also as an oncolytic peptide due to its structural and physical properties. CKS1 induced both necrotic and apoptotic cell death specifically...

Understanding the intricate interactions of cancer cells with the tumor microenvironment (TME) is a pre-requisite for the optimization of immunotherapy. Mechanistic models such as quantitative systems pharmacology (QSP) provide insights into the TME dynamics and predict the efficacy of immunotherapy in virtual patient populations/digital twins but...

Human clinical trials provided tremendous insights to advance novel systemic therapies and to improve treatment outcomes for cancer patients. The few durable treatment options have led to a critical need to advance new therapeutics in hepatocellular carcinoma (HCC). Recent human clinical trials have demonstrated that new combination of immunotherap...

Virtual patients and digital patients/twins are two similar concepts gaining increasing attention in health care with goals to accelerate drug development and improve patients’ survival, but with their own limitations. Although methods have been proposed to generate virtual patient populations using mechanistic models, there are limited number of a...

Introduction: Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between endothelial cells under normoxia and hypoxia and their response to different stimuli can guide therapies to modulate...

Red blood cell (RBC) aging manifests through progressive changes in cell morphology, rigidity, and expression of membrane proteins. To maintain the quality of circulating blood, splenic macrophages detect the biochemical signals and biophysical changes of RBCs and selectively clear them through erythrophagocytosis. In sickle cell disease (SCD), RBC...

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between anti-tumor immunity and clinical outcomes, yet such connections remain underexplored. H...

Conditionally activated molecules, such as Probody therapeutics (PbTx), have recently been investigated to improve antitumoral response while reducing systemic toxicity. PbTx are engineered to be proteolytically activated by proteases that are preferentially active locally in the tumor microenvironment (TME). Here, we perform an exploratory study u...

Inflammatory cytokine mediated responses are important in the development of many diseases that are associated with angiogenesis. Targeting angiogenesis as a prominent strategy has shown limited effects in many contexts such as cardiovascular diseases and cancer. One potential reason for the unsuccessful outcome is the mutual dependent role between...

Background Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern s...

Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic peptide derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only as an anti-angiogenic peptide but also as an oncolytic peptide due to its structural and physical properties. CKS1 induced both necrotic and apoptotic cell death specifically...

Human clinical trials are important tools to advance novel systemic therapies improve treatment outcomes for cancer patients. The few durable treatment options have led to a critical need to advance new therapeutics in hepatocellular carcinoma (HCC). Recent human clinical trials have shown that new combination immunotherapeutic regimens provide unp...

Triple-negative breast cancer (TNBC) is a particularly aggressive and invasive subtype of breast cancer that represents a major cause of death of women worldwide. Here we describe the efficacy of an integrin-binding antiangiogenic peptide in a variety of delivery methods and dosing conditions. This peptide, AXT201, demonstrated consistent anti-tumo...

Background. We study the elastic properties of the outer hair cell. The outer hair cell is a receptor cell located in the inner ear and recently considered as the major active component in the hearing process. The lateral wall of this cell is able to transmit the changes of the membrane potential into the changes of the length of the cell (Brownell...

Triple-negative breast cancer (TNBC), a highly metastatic breast cancer subtype, has limited treatment options. While a small number of patients attain clinical benefit with single-agent checkpoint inhibitors, identifying these patients before the therapy remains challenging. Here, we developed a transcriptome-informed quantitative systems pharmaco...

Although immune checkpoint blockade therapies have shown evidence of clinical effectiveness in many types of cancer, the outcome of clinical trials shows that very few patients with colorectal cancer benefit from treatments with checkpoint inhibitors. Bispecific T cell engagers (TCEs) are gaining popularity because they can improve patients’ immuno...

Generating realistic virtual patients from a limited amount of patient data is one of the major challenges for quantitative systems pharmacology modeling in immuno-oncology. Quantitative systems pharmacology (QSP) is a mathematical modeling methodology that integrates mechanistic knowledge of biological systems to investigate dynamics in a whole sy...

Spatial heterogeneity is a hallmark of cancer. Tumor heterogeneity can vary with time and location. The tumor microenvironment (TME) encompasses various cell types and their interactions that impart response to therapies. Therefore, a quantitative evaluation of tumor heterogeneity is crucial for the development of effective treatments. Different ap...

Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between normoxia and hypoxia can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial...

Objective: Vascular remodeling at the invasive tumor front (ITF) plays a critical role in progression and metastasis of triple negative breast cancer (TNBC). Therefore, there is a crucial need to characterize the vascular phenotype (i.e. changes in the structure and function of vasculature) of the ITF and tumor core (TC) in TNBC. This requires hig...

Generating realistic virtual patients from a limited amount of patient data is one of the major challenges for quantitative systems pharmacology modeling in immuno-oncology. Quantitative systems pharmacology (QSP) is a mathematical modeling methodology that integrates mechanistic knowledge of biological systems to investigate dynamics in a whole sy...

Angiogenesis is a critical step in tumor growth, development, and invasion. Nascent tumor cells secrete vascular endothelial growth factor (VEGF) that significantly remodels the tumor microenvironment through interaction with multiple receptors on vascular endothelial cells, including type 2 VEGF receptor (VEGFR2). The complex pathways initiated by...

Introduction: Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with an overall 5-year survival rate of 26%, which varies by the disease stage. Novel drug combinations involving immune checkpoint inhibitors are being investigated in clinical trials in NSCLC. In this study, we generated about 450 virtual patients that rese...

Recent advances in spatial transcriptomics (STs) enable gene expression measurements from a tissue sample while retaining its spatial context. This technology enables unprecedented in situ resolution of the regulatory pathways that underlie the heterogeneity in the tumor as well as the tumor microenvironment (TME). The direct characterization of ce...

Inflammatory cytokine mediated responses are important in the development of many diseases that are associated with angiogenesis. Targeting angiogenesis as a prominent strategy has shown limited effects in many contexts such as peripheral arterial disease (PAD) and cancer. One potential reason for the unsuccessful outcome is the mutual dependent ro...

AXT107, a collagen-derived peptide that binds integrins αvβ3 and α5β1 with high affinity, suppresses vascular endothelial growth factor (VEGF) signaling, promotes angiopoietin 2-induced Tie2 activation, and suppresses neovascularization (NV) and vascular leakage. Immunohistochemical staining for αvβ3 and α5β1 was markedly increased in NV compared w...

Introduction In contrast to other breast cancer subtypes, there are currently limited options of targeted therapies for triple-negative breast cancer (TNBC). Immense research has demonstrated that not only cancer cells but also stromal cells and immune cells in the tumor microenvironment (TME) play significant roles in the progression of TNBC. It i...

Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients and recurrence can also occur. Little is known about the inter-and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie res...

Background: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is the third-leading cause of cancer-related death worldwide. Most patients with HCC are diagnosed at an advanced stage, and the median survival for patients with advanced HCC treated with modern systemic therapy is less than 2 years. This leaves the adv...

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor 5-year survival rates, necessitating identification of novel therapeutic targets. Elucidating the biology of the tumor immune microenvironment (TiME) can provide vital insights into mechanisms of tumor progression. In this study, we developed a quantitative image proce...

Annotating cancerous regions in whole-slide images (WSIs) of pathology samples plays a critical role in clinical diagnosis, biomedical research, and machine learning algorithms development. However, generating exhaustive and accurate annotations is labor-intensive, challenging, and costly. Drawing only coarse and approximate annotations is a much e...

Quantitative systems pharmacology (QSP) models and spatial agent-based models (ABM) are powerful and efficient approaches for the analysis of biological systems and for clinical applications. Although QSP models are becoming essential in discovering predictive biomarkers and developing combination therapies through in silico virtual trials, they ar...

The recent development of genome-wide spatial transcriptomics (ST) approaches enable near single-cell gene expression profiling to infer cellular composition and intercellular interactions that drive cancer development and responses to therapy. This study applied ST on 10 surgical biospecimens from a clinical trial with neoadjuvant therapy with cab...

Recent advances in spatial transcriptomics (ST) enable gene expression measurements from a tissue sample while retaining its spatial context. This technology enables unprecedented in situ resolution of the regulatory pathways that underlie the heterogeneity in the tumor and its microenvironment (TME). The direct characterization of cellular co-loca...

Quantitative systems pharmacology (QSP) modeling is an emerging mechanistic computational approach that couples drug pharmacokinetics/pharmacodynamics and the course of disease progression. It has begun to play important roles in drug development for complex diseases such as cancer, including triple-negative breast cancer (TNBC). The combination of...

Background Concomitant inhibition of vascular endothelial growth factor (VEGF) and programmed cell death protein 1 (PD-1) or its ligand PD-L1 is a standard of care for patients with advanced hepatocellular carcinoma (HCC), but only a minority of patients respond, and responses are usually transient. Understanding the effects of therapies on the tum...

The Angiopoietin-Tie (Ang-Tie) pathway is a key signaling pathway regulating vascular stability and permeability, and it significantly intersects and crosstalk with the vascular endothelial growth factor (VEGF) signaling pathway, a major signaling pathway regulating angiogenesis and vascular permeability. Disrupted Ang-Tie and VEGF signaling is lin...

In peripheral arterial disease (PAD), the degree of endogenous capacity to modulate revascularization of limb muscle is central to the management of leg ischemia. To characterize the multiscale and multicellular nature of revascularization in PAD, we have developed the first computational systems biology model that mechanistically incorporates intr...

Angiogenesis is an important biological process involved in development, growth, reproduction, and wound healing. Dysregulation of angiogenesis is linked to many diseases, including cancer, ocular diseases, and cardiovascular diseases. Angiogenesis is a highly regulated process that involves a plethora of cells and cellular signaling events, includ...

Angiogenesis is a highly regulated multiscale process that involves a plethora of cells, their cellular signal transduction, activation, proliferation, differentiation, as well as their intercellular communication. The coordinated execution and integration of such complex signaling programs is critical for physiological angiogenesis to take place i...

Background Structured and spatial-nuanced interactions between components in tumor microenvironment (TME) regulates the efficacy of anti-tumor regimens. Insights into this orchestrated behavior in therapeutic responders and non-responders will facilitate immunotherapies. High-multiplex imaging and spatial statistics enable deep profiling of TMEs by...

Annotating cancerous regions in whole-slide images (WSIs) of pathology samples plays a critical role in clinical diagnosis, biomedical research, and machine learning algorithms development. However, generating exhaustive and accurate annotations is labor-intensive, challenging, and costly. Drawing only coarse and approximate annotations is a much e...

The ability to measure and analyze the complex dynamic multi-marker features of macrophages is critical for the understanding of their diverse phenotypes and functions in health and disease. To that end, we have recently developed a multi-pathway computational model that for the first time enables a systems-level characterization of macrophage sign...

The Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie path...

Characterizing likelihood of response to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is an important yet unmet challenge. In this study, a machine-learning framework is developed using imaging of biopsy pathology specimens to generate models of likelihood of NAC response. Developed using cross-validation (evaluable N = 6...

Quantitative systems pharmacology (QSP) models have become increasingly common in fundamental mechanistic studies and drug discovery in both academic and industrial environments. With imaging techniques widely adopted and other spatial quantification of tumor such as spatial transcriptomics gaining traction, it is crucial that these data reflecting...

Response to cancer immunotherapies depends on the complex and dynamic interactions between T cell recognition and killing of cancer cells that are counteracted through immunosuppressive pathways in the tumor microenvironment. Therefore, while measurements such as tumor mutational burden provide biomarkers to select patients for immunotherapy, they...

Background Immune checkpoint blockade therapy has clearly shown clinical activity in patients with triple-negative breast cancer, but less than half of the patients benefit from the treatments. While a number of ongoing clinical trials are investigating different combinations of checkpoint inhibitors and chemotherapeutic agents, predictive biomarke...

Macrophages are highly plastic immune cells that dynamically integrate microenvironmental signals to shape their own functional phenotypes, a process known as polarization. Here we develop a large-scale mechanistic computational model that for the first time enables a systems-level characterization, from quantitative, temporal, dose-dependent, and...

Progress in immunotherapy has resulted in explosively increased new therapeutic interventions and they have shown promising results in the treatment of cancer. Animal testing is performed to provide preliminary efficacy and safety data for drugs under development prior to clinical trials. However, translational challenges remain for preclinical stu...

Cancer immunotherapy has achieved positive clinical outcomes and is revolutionizing cancer treatment. However, cancer immunotherapy has thus far failed to improve outcomes for most “cold tumors”, which are characterized by low infiltration of immune cells and immunosuppressive tumor microenvironment. Enhancing the responsiveness of cold tumors to c...

Overwhelming evidence has shown the significant role of the tumor microenvironment (TME) in governing the triple-negative breast cancer (TNBC) progression. Digital pathology can provide key information about the spatial heterogeneity within the TME using image analysis and spatial statistics. These analyses have been applied to CD8+ T cells, but qu...

Immunotherapy has shown great potential in the treatment of cancer, however, only a fraction of patients respond to treatment and many experience autoimmune‐related side effects. The pharmaceutical industry has relied on mathematical models to study the behavior of candidate drugs and more recently, complex, whole‐body, quantitative systems pharmac...

Background T cells have been recognized as core effectors for cancer immunotherapy. How to restore the anti-tumor ability of suppressed T cells or improve the lethality of cytotoxic T cells has become the main focus in immunotherapy. Bispecific antibodies, especially bispecific T cell engagers (TCEs), have shown their unique ability to enhance the...

Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvβ3 and α5β1 integr...

Cancer immunotherapy has recently drawn remarkable attention as promising results in the clinic have shown its ability to improve the overall survival, and T cells are considered to be one of the primary effectors for cancer immunotherapy. Enhanced and restored T cell tumoricidal activity has shown great potential for killing cancer cells. Bispecif...

Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive disease with limited treatment options. Recently, the combination of the immune checkpoint inhibitor (ICI) atezolizumab (anti-PD-L1) with nab-paclitaxel was approved following a clinical trial that showed response rates in at least 43% of patients. While this approval marks...

Hepatocellular carcinoma (HCC) is a major health concern and despite efforts to screen at‐risk individuals, diagnosis often occurs at late stages when patients are no longer candidates for potentially curative therapies (i.e. surgical resection, ablation, or transplantation). For patients with advanced HCC, tyrosine kinase inhibitors (TKIs) and imm...

In triple-negative breast cancer (TNBC), the lack of therapeutic markers and effective targeted therapies result in an incurable metastatic disease associated with a poor prognosis. Crosstalks within the tumor microenvironment (TME), including those between cancer and stromal cells, affect the tumor heterogeneity, growth, and metastasis. Previously...

The survival rate of patients with breast cancer has been improved by immune checkpoint blockade therapies, and the efficacy of their combinations with epigenetic modulators has shown promising results in preclinical studies. In this prospective study, we propose an ordinary differential equation (ODE)-based quantitative systems pharmacology (QSP)...

Mathematical modeling can be used to predict the efficacy of drug therapies in liver cancer for individual patients. A team lead by Mohammad Jafarnejad at Johns Hopkins University developed a mathematical model of cellular signaling in liver cells that can predict drug interactions affecting the growth pathways in liver cells found to be responsibl...

Macrophages respond to signals in the microenvironment by changing their functional phenotypes, a process known as polarization. Depending on the context, they acquire different patterns of transcriptional activation, cytokine expression and cellular metabolism which collectively constitute a continuous spectrum of phenotypes, of which the two extr...

The angiopoietin-Tie signaling pathway is an important vascular signaling pathway involved in angiogenesis, vascular stability, and quiescence. Dysregulation in the pathway is linked to the impairments in vascular function associated with many diseases, including cancer, ocular diseases, systemic inflammation, and cardiovascular diseases. The prese...

The angiopoietin-Tie signaling pathway is an important vascular signaling pathway involved in angiogenesis, vascular stability, and quiescence. Dysregulation in the pathway is linked to the impairments in vascular function associated with many diseases, including cancer, ocular diseases, systemic inflammation, and cardiovascular diseases. The prese...

Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we...

Over the past decade, several immunotherapies have been approved for the treatment of melanoma. The most prominent of these are the immune checkpoint inhibitors, which are antibodies that block the inhibitory effects on the immune system by checkpoint receptors, such as CTLA-4, PD-1 and PD-L1. Preclinically, blocking these receptors has led to incr...

Leading causes of vision loss include neovascular age-related macular degeneration (NVAMD) and macular edema (ME), which both require frequent intravitreal injections for treatment. A safe, poly(lactic-co-glycolic acid) (PLGA)-based biodegradable polymeric microparticle (MP) delivery system was developed that encapsulates and protects a biomimetic...

The low response rate of immune checkpoint blockade in breast cancer has highlighted the need for predictive biomarkers to identify responders. While a number of clinical trials are ongoing, testing all possible combinations is not feasible. In this study, a quantitative systems pharmacology model is built to integrate immune-cancer cell interactio...