Donald Buchsbaum

University of Alabama at Birmingham | UAB · Department of Radiation Oncology

Background/Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly challenging cancer with a dismal 5-year survival rate of under 12%. More than 90% of PDAC cases involve mutations in the GTPase KRAS. Unfortunately, existing drugs targeting the RAS family, like sotorasib, exclusively address the KRAS-G12C mutation, mainly found in NSCLC. In...

Multiple types of RAS mutations activate RAS isoforms, HRAS, NRAS, or KRAS, that drive oncogenic signaling leading to uncontrolled cell proliferation and tumor development. RAS mutations occur de novo in approximately one-third of all human cancers, and are especially prevalent in pancreatic, colorectal, and lung tumors. Where RAS mutations are les...

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the U.S. This is frequently due to advanced disease at time of diagnosis as well as the high prevalence of KRAS driver mutations. Currently available targeted therapeutics are designed to covalently inactivate only KRAS-G12C mutants, whereas the most common mutation...

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds α2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A...

Here we describe a novel class of pan-RAS inhibitor with highly potent and selective anticancer activity by killing cancer cells harboring mutations in RAS or with constitutively activated RAS resulting from mutations in upstream signaling components. A lead compound from this chemical family, ADT-007, binds RAS when in a nucleotide free transition...

Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer death in the U.S. with only about a 10% five-year survival rate and an estimated 60,000 deaths/year by 2030. Poor survival is frequently due to advanced disease at the time of diagnosis, as well as the high prevalence of KRAS driver mutations. Currently, approved KRAS-targete...

Background: Pancreatic ductal adenocarcinoma (PDAC) has low (<11%) 5-year survival due to the presence of advanced disease at diagnosis. Currently standard of care provides a median survival of 1 year in the majority of patients presenting with advanced disease. Targeting oncogenic KRAS, which is mutated in >90% of human PDAC tumors, provides an op...

RAS is a critically important oncogenic protein that is mutated in approximately 1/3 of cancers resulting in aberrant activation of downstream signaling, which drives malignant transformation. Current molecular targeted therapeutics, and several in development, inhibit only specific mutant alleles (G12C, G12D). In addition, compounds which directly...

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds α2,6-linked sialic acids to N -glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A...

Mutations in the three RAS oncogenes are present in approximately 30% of all human cancers that drive tumor growth and metastasis by aberrant activation of RAS-mediated signaling. Despite the well-established role of RAS in tumorigenesis, past efforts to develop small molecule inhibitors have failed for various reasons leading many to consider RAS...

Background: In the past few years, 3D organoid cultures of patient-derived tumors or patient-derived xenografts have gained significant attention as faster and more economical ex vivo alternatives to animal models for the pre-clinical evaluation of therapeutics. We reported previously that raft cultures of ex vivo epithelial warts, normal human epi...

ST6Gal-I, an enzyme upregulated in numerous malignancies, adds α2-6-linked sialic acids to select membrane receptors, thereby modulating receptor signaling and cell phenotype. In this study, we investigated ST6Gal-I's role in epithelial to mesenchymal transition (EMT) using the Suit2 pancreatic cancer cell line, which has low endogenous ST6Gal-I an...

Breast cancers are divided into subtypes with different prognoses and treatment responses based on global differences in gene expression. Luminal breast cancer gene expression and proliferation are driven by estrogen receptor alpha, and targeting this transcription factor is the most effective therapy for this subtype. By contrast, it remains uncle...

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with an extremely poor prognosis. There is an urgent need to identify new therapeutic targets and also understand the mechanism of PDAC progression that leads to aggressiveness of the disease. To find therapeutic targets, we analyzed data related to PDAC transcriptome sequencing and fo...

Approximately 30% of human cancers harbor a gain‐in‐function mutation in the RAS gene , resulting in constitutive activation of the RAS protein to stimulate downstream signaling, including the RAS‐mitogen activated protein kinase pathway that drives cancer cells to proliferate and metastasize. RAS‐driven oncogenesis also promotes immune evasion by...

Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrel...

Background The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and muri...

Approximately 28 million people in the United States have precancerous colonic adenomas with many at high risk of developing colorectal cancer who could benefit from a pharmacological approach to prevent malignant progression. Clinical, epidemiological, and preclinical studies have reported or provided mechanistic evidence that nonsteroidal anti-in...

Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chem...

Breast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. Luminal breast cancer gene expression and proliferation are driven by the transcription factors Estrogen Receptor alpha (ER), FOXA1 and GATA3. Targeting ER is the most effective therapy for treating luminal breas...

We previously showed that a class I histone deacetylase (HDAC) inhibitor, entinostat (ENT), dramatically improves CD8 T cell-mediated control of TS/A murine mammary tumors, but only when given in a precise window. If given too early ENT halts initial T cell activation and expansion and has no effect if given too late— once T cells start becoming dy...

Background: Targeted radioimmunotherapy (RIT) is an attractive approach to selectively localize therapeutic radionuclides to malignant cells within primary and metastatic tumors while sparing normal tissues from the effects of radiation. Many human malignancies express B7-H3 on the tumor cell surface, while expression on the majority of normal tis...

The expression of MHC class II molecules (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we showed that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4⁺ and CD8⁺ T...

BACKGROUND Ovarian cancer is poorly immunogenic; however, increased major histocompatibility complex class II (MHCII) expression correlates with improved immune response and prolonged survival in patients with ovarian cancer. The authors previously demonstrated that the histone deacetylase inhibitor entinostat increases MHCII expression on ovarian...

Biomaterials engineered to closely mimic morphology, architecture, and nanofeatures of naturally occurring in vivo extracellular matrices (ECM) have gained much interest in regenerative medicine and in vitro biomimetic platforms. Similarly, microphysiological systems (MPS), such as lab-chip, have drummed up momentum for recapitulating precise biome...

Malignant cells harbor an imbalance in histone acetyltransferase and histone deacetylase (HDAC) activity, epigenetically contributing to altered cellular programs. HDAC inhibitors disrupt this balance to impact both cellular transcription and protein function, changing the phenotype of tumor cells as well as responding immune cells, including tumor...

Objective: The Wnt/β-catenin pathway is a major signal transduction pathway involved in ovarian cancer (OVCA) metastasis and resistance to chemotherapy. This pathway downregulates protective immunity mediated by intra-tumoral CD8+T cells in other cancer types. WNT974 is a novel drug that inhibits the enzyme Porcupine, which controls Wnt protein sec...

Wnt/β-catenin signaling is upregulated in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes and normal tissues. Current Wnt/β-catenin inhibitors, such as niclosamide, target the pathway nonspecifically and exhibit poor pharmacokinetics/pharmacodynamics in vivo. Niclosamide targets other pathways, including mTOR, STAT3 an...

Malignant cells often harbor an imbalance in histone acetyltransferase and histone deacetylase (HDAC) activity, which can be disrupted by HDAC inhibitors. We hypothesized that HDAC inhibition can boost anti-tumor T cell responses by modifying tumor cell phenotypes as well as directly altering the transcriptional framework of tumor-specific T cells....

[This corrects the article DOI: 10.18632/oncotarget.13466.].

The expression of major histocompatibility complex II (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we tested how MHCII expression affected anti-tumor immunity. We found that MHCII-expressing tumors grew...

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate prot...

In this issue of Blood, Green et al identified an innovative and promising pretargeted radioimmunotherapy (RIT) approach for the treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma. Pretargeted RIT of B-cell malignancies with a CD38 bispecific monoclonal antibody (mAb) is a novel approach, and the results achieved in preclinical models are...

Histone deacetylase inhibitors possess a broad array of antitumor activities; however, their net impact on the evolving antitumor immune response is highly dependent on the inhibitors used and the histone deacetylases they target. Herein, we sequentially focus on each stage of the antitumor immune response - from dendritic cell activation and migra...

Introduction: We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted α-particle radioimmunotherapy (RIT) with 212Pb in ovarian cancer mouse models. In this study, we tested the binding of radiolabeled mAb 376.96 to human pancreatic ductal adenocarcinoma (PDAC) cells and localization in xenografts in immune-defi...

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Gemcitabine, as a single agent or in combination therapy, remains the frontline chemotherapy despite its limited efficacy due to de novo or acquired chemoresistance. There is an acute need to decipher mechanisms underlying chemoresistance and identify new tar...

We recently reported that the aberrant expression of Major Histocompatibility Class II (MHCII) molecules on human triple negative breast cancer (TNBC) cells correlates with prolonged progression-free survival and increased tumor infiltrating lymphocytes. We hypothesized that the expression of MHCII enhances the intratumoral CD4+ T cell response, th...

Aberrant activation of Wnt/β-catenin signaling is a necessary initiating event in the genesis of most colorectal cancers. Loss-of-function mutations in the tumor suppressor gene adenomatous polyposis coli (APC) are present in about 80% of all colorectal cancers, and gain-of-function mutations in the oncogene CTNNB1 (β-catenin encoding gene) exist i...

Patients with triple negative breast cancer (TNBC) have no successful "targeted" treatment modality, which represents a priority for novel therapy strategies. Upregulated death receptor 5 (DR5) expression levels in breast cancer cells compared to normal cells enable TRA-8, a DR5 specific agonistic antibody, to specifically target malignant cells fo...

We recently reported that aberrant expression of Major Histocompatibility Class II (MHCII) on human triple negative breast cancer cells correlates with increased tumor infiltrating lymphocytes and prolonged progression free survival. This observation led us to hypothesize that expression of MHCII enhanced the intratumoral CD4+ T cell response, ther...

Induction of apoptosis in cancer cells has increasingly been the focus of many therapeutic approaches in oncology field. Since its identification as a TNF family member, TRAIL (TNF-related apoptosis-inducing ligand) paved a new path in apoptosis inducing cancer therapies. Its selective ability to activate extrinsic and intrinsic cell death pathways...

Expression of MHC class II pathway proteins in ovarian cancer correlates with prolonged survival. Murine and human ovarian cancer cells were treated with epigenetic modulators - histone deacetylase inhibitors and a DNA methyltransferase inhibitor. mRNA and protein expression of the MHC II pathway were evaluated by qPCR and flow cytometry. Treatment...

Background Radiogenetic therapy is a novel approach in the treatment of cancer, which employs genetic modification to alter the sensitivity of tumor cells to the effect of applied radiation. AimTo select a potent radiation inducible promoter in the context of brain tumors and to investigate if CArG radio responsive motifs or other elements in the p...

Despite a good initial response to chemotherapy, the majority of patients with epithelial ovarian cancer will eventually recur and die of their disease. The introduction of targeted therapies to traditional chemotherapy regimens has done little to improve overall survival in women with ovarian cancer. It has become increasingly apparent that the ca...

Wnt/beta-Catenin signaling pathway has a very important role in pancreatic ductal adenocarcinoma (PDAC) initiation and progression. This signaling pathway has been implicated in angiogenesis, maintenance of resistant CICs (cancer-initiating cells), metastasis, regulation of cell cycle, apoptosis and chemoresistance. We investigated the activity of...

Activation of death receptor-5 (DR5) leads to the formation of death inducing signaling complex (DISC) for apoptotic signaling. TRA-8, a DR5 specific agonistic antibody, has demonstrated significant cytotoxic activity in vitro and in vivo without inducing hepatotoxicity. Calmodulin (CaM) that is overexpressed in breast cancer plays a critical role...

Introduction: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 ep...

Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER...

Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-ca...

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of...

Since its identification as a member of the tumour necrosis factor (TNF) family, TRAIL (TNF-related apoptosis-inducing ligand) has emerged as a new avenue in apoptosis-inducing cancer therapies. Its ability to circumvent the chemoresistance of conventional therapeutics and to interact with cancer stem cells (CSCs) self-renewal pathways, amplified i...

We recently reported that the mRNA expression of genes in the Major Histocompatibility Complex class II (MHCII) antigen processing and presentation pathway in breast tumor tissues was strongly prognostic of good clinical outcome in triple negative breast cancer (TNBC) patients (J Clin Oncol 33, 2015 suppl; abstr 1066). Although MHCII expression is...

INTRODUCTION This study evaluated the potential of epigenetic treatments to induce the expression of the MHC-II antigen presentation pathway in ovarian cancer. Ovarian cancer escapes immune response allowing it to spread in the peritoneal cavity; however, patients with greater immune response to their tumors at baseline have improved survival. Typi...

Altered glycosylation is a key hallmark of tumor cells; still, the role of individual glycosyltransferases remains unclear. ST6Gal-I is a tumor-associated sialyltransferase which catalyzes the addition of a sialic acid sugar to substrate glycoproteins. Addition of the negatively-charged sialic acid by ST6Gal-I has been shown to alter receptor confo...

The glycosyltransferase ST6Gal-I which adds α2-6-linked sialic acids to substrate glycoproteins has been implicated in carcinogenesis, however, the nature of its pathogenic role remains poorly understood. Here we show that ST6Gal-I is upregulated in ovarian and pancreatic carcinomas, enriched in metastatic tumors and associated with reduced patient...

The majority of patients with epithelial ovarian cancer are diagnosed with advanced disease. While many of these patients will respond initially to chemotherapy, the majority will relapse and die of their disease. Targeted therapies that block or activate specific intracellular signaling pathways have been disappointing. In the past 15years, the ro...

Background: Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. Results: RNA seque...

Activation of death receptor-5 (DR5) leads to the formation of death inducing signaling complex (DISC) for apoptotic signaling. Targeting DR5 to induce breast cancer apoptosis is a promising strategy to circumvent drug resistance and present a target for breast cancer treatment. Calmodulin (CaM) has been shown to regulate DR5-mediated apoptotic sig...

Triple negative breast cancer (TNBC) is a subtype with heterogeneous patient outcomes. Approximately forty percent of patients experience rapid relapse, while the remaining patients have long-term disease-free survival. To determine if there are molecular differences between primary tumors that predict prognosis we performed RNA-seq on 47 macro-dis...

The expression of the tumor suppressor Merlin is compromised in nervous system malignancies due to genomic aberrations. We demonstrated for the first time, that in breast cancer, Merlin protein expression is lost due to proteasome-mediated elimination. Immunohistochemical analysis of tumor tissues from patients with metastatic breast cancer reveale...

The study goal was to examine the relationship between nab-paclitaxel delivery and SPARC (secreted protein acidic and rich in cysteine) expression in pancreatic tumor xenografts and to determine the anti-stromal effect of nab-paclitaxel, which may affect tumor vascular perfusion. SPARC positive and negative mice bearing Panc02 tumor xenografts (n=5...

Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/β-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/β-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were i...

We have applied a serologic proteomic workflow involving three complementary MS approaches to a tissue-specific Kras(G12D) -knockin mouse model of pancreatic cancer that consistently forms pre-cancerous lesions by four months of age. The three proteomics applications were highly complementary and allowed us to survey the entire range of low to high...

Purpose: The aim of the study was to develop a reliable quantitative imaging biomarker from fluorescence microscopic imaging of TRA-8/death receptor 5 (DR5) oligomer to predict TRA-8 therapeutic efficacy in human breast and pancreatic cancer mouse models. Procedures: Two breast (2LMP, SUM159) and two pancreatic (MIA PaCa-2, PANC1) cancer cell li...

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces a death signal following binding to death receptors (DR4, DR5). We have developed a novel anti-human DR-5 monoclonal antibody (TRA-8) and adenoviral encoding TRAIL (Ad/TRAIL). Herein, we are testing the combined effect of radiotherapy and TRA-8 or Ad TRAIL in prostate cancer ce...

Objective: Niclosamide, a salicyclamide derivative and FDA approved teniacide, exhibits potent effects against ovarian cancer in vitro by inhibiting the Wnt/β-catenin, STAT3, and mTOR pathways. Unfortunately, its low bioavailability as a chemotherapeutic agent in vivo necessitates investigation of analogs with improved pharmacokinetics and pharmaco...

Breast cancer is estimated to be the leading cause of new cancer cases and second in cancer related deaths among American women (Cancer: 63, 1153-1154, 2013). Classification of breast cancers into receptor-based subtypes, including estrogen receptor (ER) positive or triple negative breast cancers, establish targets that guide individualized treatme...

s: AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA The purpose of this study was to investigate the role of HER3 ligand-independent activation in EGFR resistance in pancreatic cancer. The expression and activation status of EGFR and HER3 were determined in a panel of 13 human pa...

Preclinical research in gynecologic malignancies has largely relied upon cloned cancer-derived cell lines and tumor xenografts derived from these cell lines. Unfortunately, the use of cell lines for translational research has disadvantages because genetic and phenotypic alterations from serial passaging have resulted in expression profiles that are...

Objective Niclosamide has shown activity against ovarian cancer in vitro; however, it has low bioavailability in vivo. Therefore, we investigated the cytotoxicity of niclosamide analogs in combination with carboplatin against ovarian cancer patient ascites cells and tissue slices. Materials/Methods Tumorspheres were isolated from ascites collected...

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe respiratory motion artifact in the abdominal area. Orthotopic tumor models offer advantages over subcutaneous ones, because those can reflect the primary tumor microenvironment affecting blood supply, neova...

S100A4 expression is associated with poor clinical outcomes of patients with pancreatic cancer. The effects of loss or gain of S100A4 were examined in pancreatic cancer cell lines. S100A4 downregulation remarkably reduces cell migration and invasion, inhibits proliferation, and induces apoptosis in pancreatic tumor cells. S100A4 downregulation resu...

Niclosamide has shown activity against ovarian cancer in vitro; however, it has low bioavailability in vivo. Therefore, we investigated the cytotoxicity of niclosamide analogs in combination with carboplatin against ovarian cancer patient ascites cells and tissue slices. Tumorspheres were isolated from ascites collected from patients undergoing ova...

Objective: Chemoresistance and recurrence invariably develop in the treatment of ovarian cancer, despite initial response to chemotherapy. Recent studies have shown that signal transducer and activator of transcription-3 (STAT3) signaling is associated with recurrence and development of chemoresistance in ovarian cancer. A novel small molecule, LLL...

Despite significant effort and research funds, epithelial ovarian cancer remains a very deadly disease. There are no effective screening methods that discover early stage disease; the majority of patients are diagnosed with advanced disease. Treatment modalities consist primarily of radical debulking surgery followed by taxane and platinum-based ch...

TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect for triple negative breast cancer (TNBC) in preclinical models. Tamoxifen, the standard of care for ERα-positive breast cancer, induces apoptosis via ERβ, which commonly presents in TNBC cells. The current study investigates the combination effects of TR...

Objective: Assess interaction of pazopanib, an oral antivascular endothelial growth factor inhibitor, with radiation in tumor xenograft models. Methods: Flank xenografts in female athymic nude mice of human lung cancer cell line, A549, and head and neck cancer cell line, UM-SCC-6, were allowed to grow to ∼5×5 mm. Groups were then treated with pa...