Marxa L Figueiredo

Purdue University | Purdue · Department of Basic Medical Sciences (BMS)

Gene delivery as a therapeutic tool continues to advance toward impacting human health, with several gene therapy products receiving FDA approval over the past 5 years. Despite this important progress, the safety and efficacy of gene therapy methodology requires further improvement to ensure that nucleic acid therapeutics reach the desired targets...

Background Prostate cancer is the second most common cancer and is one of the leading causes of cancer-related death among American men. ¹ Prostate cancer exhibits significant tropism for the bone and once metastasis occurs, survival rates fall rapidly compared to primary tumors. ² Bone metastasis can lead to bone loss and fractures which can sever...

Cisplatin is widely used to treat different types of cancer, but its severe side effects are the major disadvantage of this treatment. Therefore, other metals are currently the subject of research in the rational development of anticancer drugs, such as copper, that has been demonstrated to be promising in this scenario. Here, we evaluated the effe...

One of the most common metastatic sites for advanced prostate cancer is bone tissue. Treatment options for bone‐metastatic prostate cancer are currently limited, with immunogenic modulation (IMO) emerging as a possible therapeutic option. IMO involves modulation of cancer cell phenotype by sub‐lethal doses of chemotherapy, making them more suscepti...

Arthritis refers to a joint disorder which features inflammation of one or more joints within the body, often resulting in pain, stiffness, swelling and decreased range of motion of joints. There are two main forms of arthritis—osteoarthritis (OA) and rheumatoid arthritis (RA)—and they both cause damage to the joints in different ways. OA, the most...

Although ~90% of prostate cancer patients with advanced disease will exhibit bone metastasis, current therapies focus on one aspect of the disease (either the tumor or the bone), with tumor elimination being the primary goal. Prostate cancer (PCa) cells ‘hijack’ bone homeostasis by disrupting the crosstalk between critical cells within the tumor/bo...

Mesenchymal stem/stromal cells (MSCs) are a multipotent stromal cell population of interest for clinical applications in different diseases due to their ability to home to injury, differentiate into non‐hematopoietic cell lineages, and secrete paracrine factors with roles in tissue repair and immunomodulation. Although the manner in which MSCs modu...

We have examined the role of a novel targeted cytokine, interleukin-27 (IL-27), modified at the C-terminus with a dual targeting and therapeutic heptapeptide, in treating prostate cancer. IL-27 has shown promise in halting tumor growth and mediating tumor regression in several cancer models, including prostate cancer. We describe our findings on th...

Interleukin-27 (IL-27) has shown promise in halting tumor growth and mediating tumor regression in several models, including prostate cancer. We describe our findings on the effects of IL-27 on the gene expression changes of TC2R prostate adenocarcinoma cells. We utilized RNAseq to assess profile differences between empty vector control, vector del...

An analysis of the emerging patent landscape of gene therapies under development, focusing on non-viral vectors.

The ability to safely and precisely deliver genetic materials to target sites in complex biological environments is vital to the success of gene therapy. Numerous viral and nonviral vectors have been developed and evaluated for their safety and efficacy. This study will feature progress in synthetic polymers as nonviral vectors, which benefit from...

Bone‐metastasis occurs in most patients suffering from advanced prostate cancer. Treatment options for such patients are currently limited and immunogenic modulation (IMO) is emerging as a possible therapeutic option. IMO involves changes in cancer cell‐phenotype in response to treatment with sub‐clinical doses of chemotherapy which makes cells mor...

An in silico screening method generated compounds that are against laminin receptor 37 LR and their anti-cancer functions in prostate cancer cell lines are disclosed herein. A group of derivatives based on the hit compound from the in silico screening are synthesized and tested with improved IC50 value that can have relevant clinical use for prosta...

Pigment epithelium derived factor (PEDF) is regarded as an exceptionally potent inhibitor of angiogenesis. Our lab and others have used PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, vascularization, and alters malignant signaling. PEDF has been identified as a binding partner for the cancer associated protein Lamini...

There is a putative precursor to mature receptor relationship between 37 Laminin Receptor (LR) and 67 LR. As such, the pair are frequently referred to as a single entity, the 37/67 kDa Laminin Receptor (37/67 LR) and 67 LR was identified as a laminin binding entity. 37/67 LR has been of clinical interest for many years, as 37/67 LR is a prognostic...

Post translational modifications are changes to proteins that occur during or after synthesis by the ribosome. Often these modifications are necessary to form mature proteins. SUMOylation (Small Ubiquitin-like Modifier, SUMO) is a type of post translational modification that has a connection to a protein, Laminin Receptor, that contributes to the a...

p>Mesenchymal stem cells (MSCs) are a potential tool for cell therapy because of their ability to home to injury sites, modulate immune responses, promote tissue repair, among other features. MSCs can also home to tumors, similarly to how they home to injury sites, and exert modulatory functions in the tumor microenvironment. However, the mechanism...

Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Most prostate cancer related fatalities are not due to tumors at origination sites, but rather due to prostate cancer metastasis throughout the body. Although the relative 5-year survival rate for localized prostate cancer nears 100%, unfortunatel...

Immunogenic modulation is an emerging strategy for treating bone-metastatic prostate tumors, which present an altered balance between bone resorption and bone formation, with enhanced tumor growth and severe pain and fractures. There remains a critical lack of therapies that can significantly reduce tumor burden while simultaneously restoring the b...

Pigment epithelium derived factor, or PEDF, is a well-known and potent inhibitor of angiogenesis. Our lab as well as others have examined PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, promotes tumor cell differentiation, and induces tumor apoptosis. PEDF has been identified as a binding partner for the cancer associ...

Chronic forms of arthritis encompass many joint inflammatory disorders, including rheumatoid arthritis (RA), an autoimmune inflammatory disease, and osteoarthritis (OA), typically a 'wear and tear' condition that is now known to also have an inflammatory etiology. The impact of inflammation in the disease prognosis and joint degradation due to impa...

Laminin receptor (67 LR) is a 67 kDa protein derived from a 37 kDa precursor (37 LR). 37/67 LR is a strong clinical correlate for progression, aggression, and chemotherapeutic relapse of several cancers including breast, prostate, and colon. The ability of 37/67 LR to promote cancer cell aggressiveness is further increased by its ability to transdu...

Mesenchymal stem cells (MSCs) represent a promising tool for cell therapy, particularly for their antitumor effects. This cell population can be isolated from multiple tissue sources and also display an innate ability to home to areas of inflammation, such as tumors. Upon entry into the tumor microenvironment niche, MSCs promote or inhibit tumor pr...

Discussion of how autocrine IL-27 in the bone immunological niche links TLR and bone homeostasis.

Laminin receptor (LR) is a protein overexpressed in cancer. LR contributes to tumor-cell migration and proliferation, and restructures laminins to increase aggressiveness and gene expression of tumor cells. Thus, the abundance of the receptor is a reliable determinant of tumor severity. Little is understood about how LR enhances aggressiveness of t...

Pigment epithelium derived factor (PEDF) is regarded as an exceptionally potent inhibitor of angiogenesis. Our lab and others have used PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, vascularization, and alters malignant signaling. PEDF has been identified as a binding partner for the cancer associated protein Lamini...

Osteoarthritis affects over 27 million Americans age 25 and older and is a debilitating disease in which articular cartilage degradation leads to inflammation and pain in the joint. Medical management has not been very successful, as cartilage is avascular and has a difficult time regenerating itself. In joints, there are laminin receptors (LR) whi...

The number of mesenchymal stem cell (MSC) therapeutic modalities has grown in recent years. Adipose-derived mesenchymal stem/stromal cells (ASCs) can be isolated and expanded relatively easily as compared with their bonemarrow counterparts, making them a particularly promising source of MSCs. And although the biological mechanisms surrounding ASCs...

Remission of inflammation has become an achievable goal in inflammatory or rheumatoid arthritis (RA); however, bone erosion continues in many patients. Interleukin- (IL-) 27 regulates immune and bone cell balance and also suppresses activities of several inflammatory cell types in RA. Despite its promise, challenges to clinical translation of IL-27...

We have utilized hidden Markov models using HMMER software to predict and generate putative strong secretory signal peptide sequences for directing efficient secretion of cytokines from skeletal muscle for therapeutic applications. The results show that this approach can analyze signal sequences of a skeletal muscle secretome dataset and classify t...

Pigment epithelium derived factor (PEDF) is regarded as an exceptionally potent inhibitor of angiogenesis. Our lab and others have used PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, vascularization, and alters malignant signaling. Recently, PEDF was identified as a binding partner for the cancer associated protein L...

Pigment epithelium derived factor (PEDF) is regarded as an exceptionally potent inhibitor of angiogenesis. Our lab and others have used PEDF as a novel prostate cancer therapy, as PEDF inhibits tumor establishment, vascularization, and alters malignant signaling. Recently, PEDF was identified as a binding partner for the cancer associated protein L...

Adipose derived mesenchymal stem/stromal cells (ASC) are emerging as a promising therapeutic strategy for the treatment of a variety of cancers. Largely, this is due to their ease of isolation and expansion, their immunological tolerance, and a unique tropism towards tumors. These qualities have allowed researchers to explore genetic modification o...

Background: The tumor microenvironment plays in an important role in the progression of cancer by mediating stromal-epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate can...

Successful gene delivery to skeletal muscle is a desirable goal, not only for treating muscle diseases, but also for immunization, treatment of metabolic disorders, and/or delivering gene expression that can treat systemic conditions, such as bone metastatic cancer, for example. Although naked DNA uptake into skeletal muscle is possible, it is larg...

Activating mutations of the ras protooncogene is the most frequent and an early genetic alteration associated with pancreatic cancer. To examine the link between mutant ras oncogenes and exocrine pancreatic cancer, and to develop mouse models of PanINs and also of lesions that progress to malignancy, we generated transgenic mice expressing either K...

The non‐integrin laminin receptor (LAMR1) is a multifunctional protein localized in the cytosol and at the membrane. Recently, the potent antiangiogenic protein required for retinal development and maintenance, pigment epithelium derived factor (PEDF), was confirmed as a binding partner for LAMR1. LAMR1 is frequently overexpressed in cancer cells....

Intracellular Ca2+ oscillations are frequently observed during stem cell differentiation, and there is evidence that it may control adipogenesis. The transient receptor potential melastatin 4 channel (TRPM4) is a key regulator of Ca2+ signals in excitable and non-excitable cells. However, its role in human adiposederived stem cells (hASCs), in part...

Intracellular Ca2+ oscillations are frequently observed during stem cell differentiation and there is evidence that it may control adipogenesis. The Transient Receptor Potential Melastatin 4 channel (TRPM4) is a key regulator of Ca2+ signals in excitable and non-excitable cells. However, its role in human adipose-derived stem cells (hASCs), in part...

The success of nonviral transfection using polymers hinges on efficient nuclear uptake of nucleic acid cargo and overcoming intra- and extracellular barriers. By incorporating PKKKRKV heptapeptide pendent groups as nuclear localization signals (NLS) on a polymer backbone, we demonstrate protein expression levels higher than those obtained from JetP...

Adipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of exp...

We have examined the role of a novel cytokine, interleukin-27 (IL-27), in mediating interactions between prostate cancer and bone. IL-27 is the most recently characterized member of the family of heterodimeric IL-12-related cytokines and has shown promise in halting tumor growth and mediating tumor regression in several cancer models, including pro...

Prostate cancer is frequently associated with bone metastases, where the crosstalk between tumor cells and key cells of the bone microenvironment (osteoblasts, osteoclasts, immune cells) amplifies tumor growth. We have explored the potential of a novel cytokine, interleukin-27 (IL-27), for inhibiting this malignant crosstalk, and have examined the...

Elevations in the intracellular Ca(2+) concentration are a phenomena commonly observed during stem cell differentiation but cease after the process is complete. The Transient Receptor Potential Melastatin 4 (TRPM4) is an ion channel that controls Ca(2+) signals in excitable and non-excitable cells. However, its role in stem cells remains unknown. T...

Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirusclosely related to murine leukemia viruses, which cause a variety of cancersand immunological and neurological diseases in mice. Whether XMRV plays a rolein cancer and other diseases remains controversial; some studies show apossible association, but there is currently no evidence...

It is critical to develop new therapeutic approaches for prostate cancer, since there is no effective treatment for patients in the advanced stages of this disease. And although many gene therapy approaches have been evaluated to date, clinical responses unfortunately remain poor. We have examined the potential of developing more effective cell-bas...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Oral squamous cell carcinoma (OSCC) affects about 30,000 Americans each year, and although the overall prognosis has improved in recent years for localized carcinomas, metastases can decrease survival rates by half. For tongue and palate lesions, surgery is usually the i...

This paper focuses on novel approaches in the field of nanotechnology-based carriers utilizing ultrasound stimuli as a means to spatially target gene delivery in vivo, using nanoparticles made with either poly(lactic-co-glycolic acid) (PLGA) or other polymers. We specifically discuss the potential for gene delivery by particles that are echogenic (...

Mouse hepatocarcinogenesis is associated with mutations in Hras, but infrequently in Kras. The effect on carcinogenesis of developmental age at the time of ras mutation remains unknown. We sought to compare quantitatively the effects of expressing mutant H- or Kras genes in fetal vs. adult mouse liver. We established an inducible system of gene exp...

We will focus on the therapeutic applications of ultrasound (US) for gene transfection or 'sonoporation'. Sonoporation therapy or 'sonotherapy' is an emerging physical method for delivering drugs and/or nucleic acids for treating cancer. Because of its non-invasive nature, sonotherapy has the potential to be competitive with other treatment deliver...

We have examined the potential of a novel cytokine, interleukin-27 (IL-27), for gene therapy of prostate cancer. IL-27 is the most recently characterized member of the family of heterodimeric IL-12-related cytokines and has shown promise in halting tumor growth and mediating tumor regression in several cancer models. In the present study, we examin...

Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus closely related to murine leukemia viruses, which cause a variety of cancers and immunological and neurological diseases in mice. Whether XMRV plays a role in cancer and other diseases remains controversial; some studies show a possible association, but there is currently no evid...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Oral squamous cell carcinoma (OSCC) affects about 30,000 Americans each year, and although the overall prognosis has improved in recent years for localized carcinomas, metastases can decrease survival rates by half. For tongue and palate lesions, surgery is usually the initia...

Adipose-derived stromal/mesenchymal stem cells (ASC) have gained interest as promising tools for delivering cancer therapy. Adipose tissue can be obtained readily in amounts sufficient for ASC isolation, which can be expanded rapidly, allowing its use at low passage numbers, and can be transduced by viral and nonviral means. Our goal was to examine...

This chapter reviews the principle, transfer techniques, therapeutic strategies, preclinical and clinical applications and limitations of gene therapy in the management of oral squamous cell carcinoma (SCC) or oral cancer. Viruses have typically been the most used transfer system for the delivery of oral cancer gene therapy. The viral vectors commo...

Intracellular Ca2+ oscillations are abundant during stem cell differentiation but cease at the termination of the differentiation process. The Transient Receptor Potential Melastatin 4 (TRPM4) ion channel is critical for Ca2+ signaling in both excitable and non-excitable cells. However, its role in stem cells has not been addressed. Objectives: We...

We examined whether the novel cell-cycle regulator cdk2-associated protein 1 (p12(cdk2ap1) or cdk2ap1), recently shown to regulate prostate cancer cell cycle and apoptosis, could have the capacity to reduce invasiveness and/or reduce malignant biological interactions between prostate cancer and bone cells. We also examined whether combining two cel...

Elevation in the intracellular Ca(2+) concentration stimulates glucagon secretion from pancreatic α-cells. The Transient Receptor Potential Melastatin 4 channel (TRPM4) is critical for Ca(2+) signaling. However, its role in glucagon secreting α-cells has not been investigated. We identified TRPM4 gene expression and protein in the αTC1-6 cell line...

We evaluated the effect of expressing the cell cycle regulator protein cdk2-associating protein1 (cdk2ap1) in inhibiting growth of squamous cell carcinoma (SCC). Expression of cdk2ap1 correlated with reduction in several SCC malignant cell phenotypes, including reduced angiogenesis. We observed several alterations in gene expression consistent with...

Unlabelled: Gene changes can affect cancer cells in many ways, but changes that increase disease severity--by allowing cells to proliferate when they should be quiescent, by enhancing their rate of growth under growth permissive conditions, or by increasing the risk that they will accumulate additional carcinogenic alterations--must be identified...

INTRODUCTION The monitoring of reporter gene expression allows measurement of the location(s), magnitude, and time variation of gene transcription in living animals and humans. Several imaging modalities can be employed for repetitive, noninvasive monitoring of reporter gene expression. The most common methods include positron emission tomography (...

Although most prostate cancers respond well to initial treatments, a fraction of prostate cancers are more aggressive and will recur and metastasize. At that point, there are few treatment options available. Significant efforts have been made to identify biomarkers that will identify these more aggressive cancers to tailor a more vigorous treatment...

The transient receptor potential melastatin type 7 channel (TRPM7) is a member of the TRP family of ion channels that is essential for cell proliferation and viability. Mesenchymal stem cells (MSCs) from bone marrow are a potential source for tissue repair due to their ability to differentiate into specialized cells. However, the role of TRPM7 in s...

We evaluated the effect of expressing the cell cycle regulator cdk2ap1, downregulated in prostate cancer cell lines, in inhibiting prostate cancer cell growth. Expression of cdk2ap1 using a tet-inducible lentiviral system modified growth rate, induced cell cycle arrest and apoptosis and reduced the invasive ability of prostate cancer cell lines, as...

Polycomb group protein enhancer of zeste 2 (EZH2) is a master regulatory protein that plays a critical role in development as part of the polycomb repressive complex 2. Polycomb repressive complex 2 controls numerous cell cycle and regulatory genes through trimethylation of histone 3, which results in chromatin condensation and transcriptional sile...

We evaluated the effect of expressing the cell cycle regulator cdk2ap1 in epithelial or stromal cell compartments to reduce SCC growth in vitro and in vivo. Cell-autonomous and/or non-cell-autonomous expression of cdk2ap1 reduced tumor growth and invasion and altered cell cycle, adhesion, invasion, angiogenesis, and apoptotic gene expression, as as...

Effective treatment for recurrent, disseminated prostate cancer is notably limited. We have developed adenoviral vectors with a prostate-specific two-step transcriptional amplification (TSTA) system that would express therapeutic genes at a robust level to target metastatic disease. The TSTA system employs the prostate-specific antigen (PSA) promot...

Treating recurrent prostate cancer poses a great challenge to clinicians. Research efforts in the last decade have shown that adenoviral vector-based gene therapy is a promising approach that could expand the arsenal against prostate cancer. This maturing field is at the stage of being able to translate many preclinical discoveries into clinical pr...

The novel cell-cycle regulator p12(CDK2AP1) (p12) gene encodes a cyclin-dependent kinase 2 (CDK2) partner that participates in cell-cycle regulation, apoptosis, and proliferation. CDK2 has been implicated in maintenance of gonadal homeostasis, as knockout mice display reproductive abnormalities. To investigate the role of p12 in homeostasis of gona...

Significant advances in gene therapy have been made as a result of the improvement of gene delivery systems, discovery of new therapeutic genes, better understanding of mechanisms of disease progression, exploration and improvement of tissue-specific gene regulatory sequences, and development of better prodrug/enzyme systems. This review discusses...

Molecular Therapy (2006) 13, S245|[ndash]|S246; doi: 10.1016/j.ymthe.2006.08.714 638. The Optimal Placement and Orientation of the Bipartite Two-Step Transcription Amplification (TSTA) Expression System in Adenoviral Vectors for Prostate Cancer Gene Therapy Marxa L. Figueiredo1, Makoto Sato1,|[ast]|, May N. Chen1, Russell Powell1, Michael Carey1,...

p12(CDK2-AP1) (p12) is a CDK2-associated protein that negatively regulates its kinase activity. Growth arrest of normal diploid cells by contact inhibition resulted in an induction of p27(kip1) and reduction of CDK2 levels. Interestingly, we observed concomitantly in growth-arrested cells, there was a reduction of nuclear p12 and the appearance of...

To test the potential of p12(CDK2-AP1) (p12), a cell cycle regulator and cyclin-dependent kinase-2-associating protein commonly down-regulated in head and neck squamous cell carcinoma ( approximately 70%), as a gene therapy in inhibiting head and neck squamous cell carcinoma growth in vivo. We addressed the effect of p12 expression on tumor growth...

Silvio Gutkind – National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD, USA Head and neck cancer is the sixth most frequent cancer worldwide and the five-year survival rate remains among the lowest of the major cancers. Alterations in cellular molecules controlling DNA repair, proliferation, apoptosis, i...

The DNA-bending protein TF1 is the Bacillus subtilis bacteriophage SPO1-encoded homolog of the bacterial HU proteins and the Escherichia coli integration host factor. We recently proposed that TF1, which binds with high affinity (K d was ∼3 nm) to preferred sites within the hydroxymethyluracil (hmU)-containing phage genome, identifies its binding s...