Archive for the ‘Antiagiogenesis’ Category

Normalizing tumor blood vessels improves delivery of only the smallest nanomedicines

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Posted 09 Apr 2012 — by James Street
Category Antiagiogenesis, antiangiogenesis, NanoTechnology, Physics and Engineering
Posted: Apr 9th, 2012
(Nanowerk News) Combining two strategies designed to improve the results of cancer treatment – antiangiogenesis drugs and nanomedicines – may only be successful if the smallest nanomedicines are used. A new study from Massachusetts General Hospital (MGH) researchers, appearing in Nature Nanotechnology (“Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner”), finds that normalizing blood vessels within tumors, which improves the delivery of standard chemotherapy drugs, can block the delivery of larger nanotherapy molecules.
“We found that vascular normalization only increases the delivery of the smallest nanomedicines to cancer cells,” says Vikash P. Chauhan, of the Steele Laboratory of Tumor Biology in the MGH Radiation Oncology Department, lead author of the report. “We also showed that the smallest nanomedicines are inherently better than larger nanomedicines at penetrating tumors, suggesting that smaller nanomedicines may be ideal for cancer therapy.”
Tumors need to generate their own blood supply to continue growing, but vessels supplying tumors tend to be disorganized, oversized and leaky. Not only does this prevent the delivery of chemotherapy drugs to cells not close to tumor vessels, but the leakage of plasma out of blood vessels increases pressure within the tumor, further reducing the ability of drugs to penetrate tumors. Treatment with drugs that inhibit angiogenesis – the process by which new vessels are generated – reduces some of these abnormalities, a process called vascular normalization that has been shown to improve treatment of some cancers with standard chemotherapy drugs.
Nanomedicines are actually designed to exploit tumor vessel abnormality. While the molecules of standard chemotherapy drugs are about one nanometer – a billionth of a meter – nanomedicine molecules are from 10 to 100 times larger, too large to penetrate the pores of blood vessels in normal tissues but small enough to pass through the oversized pores of tumor vessels. Since the size of nanomedicines should keep them out of normal tissues, they are prescribed to reduce the negative side effects of chemotherapy.
The current study was designed to investigate whether the use of antiangiogenesis drugs to normalize tumor vasculature would improve or impede delivery of nanomedicines to tumor cells. In studies using a mouse model of breast cancer, the investigators first confirmed that treatment with DC101, an antibody to a molecule essential to blood vessel growth, temporarily decreased the diameter of enlarged tumor blood vessels. They then showed that this vascular normalization improved the penetration into tumors of 12-nanometer particles but not of 60- or 125-nanometer molecules.
A mathematical model prepared by the MGH team predicted that, while the abnormally large pores in the walls of tumor blood vessels lead to increased pressure within the tumor that impedes the entry of drugs, reducing pore size by antiangiogenesis treatment would relieve intratumor pressure, allowing the entry of those molecules that fit through the smaller pores. To test this prediction, they treated mice with implanted breast tumors either with DC101 and Doxil, a 100-nanometer version of the chemotherapy drug doxorubicin, or with DC101 and Abraxane, a 10-nanometer version of paclitaxel. Although treatment with both chemotherapeutics delayed tumor growth, vascular normalization with DC101 improved the effectiveness only of Abraxane and had no effect on Doxil treatment.
“A variety of anticancer nanomedicines are currently in use or in clinical trials,” says Chauhan, who is a graduate student at the Harvard School of Engineering and Applied Sciences (SEAS). “Our findings suggest that combining smaller nanomedicines with antiangiogenic therapies may have a synergistic effect and that smaller nanomedicines should inherently penetrate tumors faster than larger nanomedicines, due to the physical principles that govern drug penetration. While it looks like future development of nanomedicines should focus on making them small – around 12 nanometers in size – we also need to investigate ways to improve delivery of the larger nanomedicines that are currently in use.”
“Antiangiogenic agents are prescribed to a large number of cancer patients in combination with conventional therapeutics,” explains Rakesh K. Jain, PhD, director of the Steele Lab and senior and corresponding author of the Nature Nanotechnology report. “Our study provides guidelines on how to combine the antiangiogenic drugs with nanotherapeutics.” Jain is Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School.

N-acetyl-cysteine (NAC)–is an anticarcinogenic and antimutagenic agent

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Posted 21 Nov 2011 — by James Street
Category Antiagiogenesis, Metastases, metastases, N-acetylcisteine

N-acetyl-cysteine (NAC)–is an anticarcinogenic and antimutagenic agent; it inhibits IL-6 as well as invasion and metastasis of malignant cells
N-acetyl-cysteine (NAC) is the acetylated precursor of the amino acids L-cysteine and reduced glutathione. Historically, it is used as a mucolytic agent in respiratory illnesses as well as an antidote for acetaminophen hepatotoxicity, but more recently its credits have grown. Animal and human studies have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer (Bongers et al. 1995; van Zandwijk 1995).

The biological value of NAC is attributed to its sulfhydryl group, while its acetyl-substituted amino group offers protection against oxidative and metabolic processes (Bonanomi et al. 1980; Sjodin et al. 1989). In vitro studies showed NAC to be directly antimutagenic and anticarcinogenic; in vivo, NAC inhibited mutagenicity of a number of mutagenic materials (De Flora et al. 1986, 1992).

NAC has both chemopreventive and therapeutic potential in malignancies arising in the lung, skin, breast, liver, head, and neck (van Zandwijk 1995; Izzotti 1998). NAC is effective in inhibiting tumor cell growth in melanoma, prostate cells, and astrocytoma cell lines (the latter is a primary tumor in the brain) (Albini et al. 1995; Arora-Kuruganti et al. 1999; Chiao et al. 2000). Neovascularization (new blood vessel growth) is crucial for tumor mass expansion and metastasis. NAC inhibited invasion and metastasis of malignant cells by up to 80% by preventing angiogenesis (De Flora et al. 1996).

A number of cancers express IL-6 and other potentially dangerous cytokines. NAC inhibited (in a dose-dependent manner) the synthesis of IL-6 by alveolar macrophage (Munoz et al. 1996; Gosset et al. 1999).

Peak plasma levels of NAC occur approximately 1 hour after an oral dose; 12 hours after dosing, it is undetectable. Despite a relatively low bioavailability (4-10%), research has shown NAC to be clinically effective (Borgstrom et al. 1986). A suggested NAC therapeutic dosage is usually in the range of 600 mg per day.

Lactoferrin–is immunoregulatory, inhibits angiogenesis, and binds iron

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Posted 21 Nov 2011 — by James Street
Category Antiagiogenesis, antiangiogenesis, lactoferrin

Lactoferrin–is immunoregulatory, inhibits angiogenesis, and binds iron
Perhaps one of the most promising therapeutic uses of lactoferrin, a milk protein with bacteriostatic properties, may be as a nontoxic, anticancer agent. Lactoferrin, a minor fraction of whey, results in a significant reduction in the incidence of esophageal, lung, bladder, and colon cancer in laboratory rats (Ushida et al. 1999; Masuda et al. 2000; Tsuda et al. 2002).

Since evidence indicates milk products protect against colon cancer, researchers speculate that bovine lactoferrin, a natural ingredient in milk, may be the chemoprotective agent (Tsuda et al. 2000b). Rats treated with a carcinogen and supplemented with 2% bovine lactoferrin for 36 weeks had a reduced incidence of colon cancer (27% of that observed in a control group; rats receiving 0.2% bovine lactoferrin reduced incidence to 46%). A remarkable 43% reduction in spontaneous lung metastasis (compared to controls) occurred after implanting colon carcinoma 26 (Co 26 Lu) in lactoferrin-treated laboratory animals (Tsuda et al. 2000a).

In addition to inhibiting angiogenesis (the vascular network that sustains the tumor), lactoferrin maintains the integrity of the immune system (Yoo et al. 1997; Tsuda et al. 2002). Typically, bovine lactoferrin prompts an increase in the number of natural killer cells, as well as the cytotoxicity of white blood cells (Tsuda et al. 2000a). The antibiotic, anti-inflammatory, and immune-modulating properties of lactoferrin appear active against the gastritis-, ulcer-, and cancer-inducing bacterium Helicobacter pylori (Dial et al. 2002).

Lactoferrin, a natural iron-binding protein, scavenges free radicals in fluids and inflamed areas, suppressing free radical mediated damage. It decreases the availability of iron in neoplastic cells, depriving them of an iron supply (Khan et al. 2001; Weinberg 2001).

The suggested dosage is 300-900 mg a day of the superior apolactoferrin (iron-depleted) form of lactoferrin. Lactoferrin is a natural component of cows’ and human mothers’ milk, but is also found in the milk of sheep, goats, and pigs.

Researchers gain new insights into how tumor cells are fed

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Posted 08 Aug 2011 — by James Street
Category Antiagiogenesis, antiangiogenesis

Contact: David Sampson
ajpmedia@elsevier.com
215-239-3171
Elsevier Health Sciences

Shows promise for development of anti-tumor drugs

Philadelphia, PA, August 8, 2011 – Researchers have gained a new understanding of the way in which growing tumors are fed and how this growth can be slowed via angiogenesis inhibitors that eliminate the blood supply to tumors. This represents a step forward towards developing new anti-cancer drug therapies. The results of this study have been published today in the September issue of The American Journal of Pathology.

“The central role of capillary sprouting in tumor vascularization makes it an attractive target for anticancer therapy. Our observations suggest, however, that targeting just this mode of blood vessel formation may not be sufficient to result in a significant antitumor effect,” commented lead investigators Sándor Paku, PhD, Semmelweis University, Budapest, and Balazs Dome, MD, PhD, Medical University of Vienna.

Investigators from the Semmelweis University, the National Institute of Oncology, and the National Koranyi Institute of Pulmonology, Budapest, Hungary, and the Medical University of Vienna, Vienna, Austria, used electron and confocal microscopy to examine tumor tissue in mice in which malignant tumor cells had been introduced. They proposed a novel mechanism for the development of tissue pillars (the most characteristic feature of intussusceptive angiogenesis, in which a vessel folds into itself to form two vessels). Moreover, they demonstrated a significant increase in pillar formation after treatment with the angiogenesis inhibitor vatalanib. Their observations support the notion that inhibition of just a single tumor vascularization mechanism can trigger alternative ones.

Prior to this study, the mechanism of pillar formation had not been fully understood. Investigation revealed a progression of events that generates a connection between the processes of endothelial bridging and intussusceptive angiogenesis resulting in rapid pillar formation from pre-existing building blocks. To describe this mechanism of pillar formation the group coined the term “inverse sprouting.”

“It is well established now that tumors can obtain sufficient blood supply from alternative vascularization mechanisms (such as intussusceptive angiogenesis) to grow without capillary sprouting (known as the key mode of new vessel formation in cancer). Therefore, antiangiogenic therapies should be tailored depending on the angiogenic phenotype in each single tumor, and the targeting of non-sprouting angiogenic mechanisms in cancer seems to be a rational strategy. Our study provides new understanding of cancer-induced intussusceptive angiogenesis and may serve as a basis for the development of novel drugs targeting this type of blood vessel formation.”

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The article is “A New Mechanism for Pillar Formation during Tumor-Induced Intussusceptive Angiogenesis,” by Sándor Paku, Katalin Dezsö, Edina Bugyik, József Tóvári, József Tímár, Péter Nagy, Viktoria Laszlo, Walter Klepetko, and Balázs Döme (doi: 10.1016/j.ajpath.2011.05.033). It will appear in The American Journal of Pathology, Volume 179, Issue 3 (September 2011) published by Elsevier.

VEGFA gene amplification associated with poor prognosis in osteosarcoma

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Posted 19 Apr 2011 — by James Street
Category Antiagiogenesis, genetic, genetic research, genetic research, Human osteosarcoma research, Local Recurrence, Lung Metastases, Metastases, Osteosarcoma, Osteosarcoma Outcomes
Posted April 18, 2011

Yang J. Cancer. 2011;doi:10.1002/cncr.26116.

Results from an analysis of tissue sections from 58 patients with osteosarcoma show that the vascular endothelial growth factor pathway genes, including VEGFA, are amplified in osteosarcoma.

VEGFA amplification is a poor prognostic factor for tumor-free survival, as well as an important mechanism for elevated VEGFA protein expression.

Researchers collected clinicopathologic data and formalin-fixed, paraffin-embedded tissue sections from 58 patients treated for primary, conventional, central osteosarcoma at the Tianjin Medical University Cancer Institute and Hospital in Tianjin, China. To identify the altered pathways, researchers analyzed recurrent amplified and deleted genes using the Kyoto Encyclopedia of Genes and Genomes.

Researchers identified 33 key pathways with multiple component genes altered at the chromosome level. These pathways included the VEGF signaling, mammalian target of rapamycin, cellular adhesion molecule, adherens junction, Wnt and hedgehog signaling pathways. The VEGF pathway was most frequent, with 13 amplified genes, including VEGFA.

“Abundant” expression of VEGFA was noted in 74.1% of patients with osteosarcoma. Further analysis showed that VEGFA gene amplification had a strong correlation with abundant VEGFA protein expression, which researchers said suggests that VEGFA gene amplification contributes to the elevated expression of VEGFA and vascular features in osteosarcoma, and poorer survival. A survival analysis on patients with VEGFA gene amplification showed that DFS rates were lower in this group.

Researchers then stratified patients into low and high VEGFA groups. Those in the high group had both VEGFA gene amplification and positive VEGFA protein expression. Kaplan-Meier analysis showed that tumor-free survival rates were worse for patients in the high VEGFA group (P=.037).

Yang and colleagues said the pattern of overall copy number alterations from their microarray-based comparative genomic hybridization dataset was surprisingly similar to that of patients evaluated in Canada and Norway, which suggests that issues of small sample size frequently associated with most cancer types may not be so serious for osteosarcoma.

Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines

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Posted 12 Apr 2011 — by James Street
Category Antiagiogenesis, CURCUMIN, Dog Osteosarcoma, genetic research, Metastases, Osteosarcoma, STAT3

We have previously demonstrated that both canine and human OSA cell lines, as well as 8 fresh canine OSA tumor samples, exhibit constitutive phosphorylation of STAT3, and that this correlates with enhanced expression of matrix metalloproteinase-2 (MMP2). While multiple signal transduction pathways can result in phosphorylation of STAT3, stimulation of the cytokine receptor gp130 through either IL-6 or Oncostatin M (OSM) is the most common mechanism through which STAT3 is activated.

The purpose of this study was to evaluate the role of IL-6 and OSM stimulation on both canine and human OSA cell lines to begin to determine the role of these cytokines in the biology of OSA.

Methods: RT-PCR and Western blotting were used to interrogate the consequences of OSM and IL-6 stimulation of OSA cell lines. OSA cells were stimulated with OSM and/or hepatocyte growth factor (HGF) and the effects on MMP2 activity (gel zymography), proliferation (CyQUANT), invasion (Matrigel transwell assay), and VEGF production (Western blotting, ELISA) were assessed.

The small molecule STAT3 inhibitor LLL3 was used to investigate the impact of STAT3 inhibition following OSM stimulation of OSA cells.

Results: Our data demonstrate that the OSM receptor (OSMR), but not IL-6 or its receptor, is expressed by all human and canine OSA cell lines and canine OSA tumor samples; additionally, OSM expression was noted in all tumor samples. Treatment of OSA cell lines with OSM induced phosphorylation of STAT3, Src, and JAK2.

OSM stimulation also resulted in a dose dependent increase in MMP2 activity and VEGF expression that was markedly reduced following treatment with the small molecule STAT3 inhibitor LLL3. Lastly, OSM stimulation of OSA cell lines enhanced invasion through Matrigel, particularly in the presence of rhHGF.

In contrast, both OSM and HGF stimulation of OSA cell lines did not alter their proliferative capacity.

Conclusions: These data indicate OSM stimulation of human and canine OSA cells induces STAT3 activation, thereby enhancing the expression/activation of MMP2 and VEGF, ultimately promoting invasive behavior and tumor angiogenesis. As such, OSM and its receptor may represent a novel target for therapeutic intervention in OSA.

Author: Stacey FosseyMisty BearWilliam KisseberthMichael PennellCheryl London
Credits/Source: BMC Cancer 2011, 11:125

Lombardi research teams hone in on treatments for osteosarcoma and Ewing’s sarcoma

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Posted 21 Jan 2011 — by James Street
Category Antiagiogenesis, Dog Osteosarcoma, Finance and Politics of cancer research and treatment, genetic research, Human osteosarcoma research, Local Recurrence, Lung Metastases, Molecular Osteosarcoma Studies, Osteosarcoma, Osteosarcoma Outcomes, Osteosarcoma Treatment Centers

Washington, DC – Most cancers arise from the epithelium, the tissue that lines the body and the organs, but sarcomas come from connective tissue cells, like the bones. At Georgetown Lombardi Comprehensive Cancer Center, research have engaged in a full-court press to develop new therapies to treat osteosarcoma and Ewing’s sarcoma, the two most common bone tumors in children, adolescents and young adults.

At the AACR 101st Annual Meeting 2010, they offer new molecular insights into the translocation that causes Ewing’s sarcoma, a genetic exchange between chromosomes that results in a fused gene that produces an oncogenic protein. These findings, coupled with use of sophisticated drug design technology, have led to identification of three new targets for potential treatment of this rare cancer. Additionally, researchers have identified two small molecules that have the potential to prevent or treat spread of osteosarcoma, a very aggressive cancer. (Embargoes listed with each abstract summary that follows).

“Scientific studies in the past decade identified very promising molecular targets that play a major role in tumor progression and invasion. With the help of a multidisciplinary team of scientists at Lombardi, we are now focusing on developing small molecules that can hit these targets,” says Aykut Üren, M.D., assistant professor in the Department of Oncology at Lombardi. “With this truly translational experimental approach, we may be able to optimize our small molecules for clinical trials in the near future.”

Original article: http://www.eurekalert.org/pub_releases/2010-04/gumc-lrt040710.php

Pervasis Therapeutics to Develop Novel Cell-Based Approach to Target Tumor Environment, Prevent Cancer Recurrence

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Posted 20 Jan 2011 — by James Street
Category Antiagiogenesis, antiangiogenesis, antiinflammatory, Inflamation, Local Recurrence, Lung Metastases, Metastases, metastases, Molecular, Personalized, Prostate Cancer, Targeted Cancer Therapy

Bolstered by Landmark Research and Multiple Preclinical Studies, Groundbreaking Therapy Holds Promise to Deliver Safe, Effective Cell Therapy Treatment for Solid Tumors

CAMBRIDGE, Mass., Jan. 19, 2011 /PRNewswire/ — Pervasis Therapeutics, Inc. today announced that the company is pursuing a matrix-embedded endothelial cell-based therapy (PVS-30200) to target and regulate cell stroma (the tumor environment or “ecosystem” that is comprised of various supporting cell types distinct from cancer cells) in order to prevent key processes that play a role in advancing solid tumor growth and metastasis (the spread of cancer cells to secondary locations). A cornerstone of Pervasis’ oncology program, the company has entered into an exclusive patent license agreement with the Massachusetts Institute of Technology (MIT) for all discovery and development activities associated with cellular implants for cancer diagnosis, prognosis and treatment. In addition, supportive evidence from multiple preclinical studies demonstrates the powerful anti-angiogenic, anti-proliferative and anti-inflammatory properties of this endothelial cell-based approach in the presence of various solid tumor cancers, such as brain, lung, breast and prostate.

Pervasis, a clinical stage company based in Cambridge, Mass., is focused on developing breakthrough cell-based therapies that harness the healing power of the endothelium, the thin layer of cells that lines the interior surface of every blood vessel in the body. The company’s other areas of clinical investigation include improving outcomes following common vascular surgical and interventional procedures, such as hemodialysis access, angioplasties, stents and peripheral and coronary bypass grafts — the failures of which result in serious complications and a significant increase in medical costs.

“We are very excited to expand our focus to include the critical area of oncology,” stated Frederic Chereau, president and chief executive officer of Pervasis. “We already have amassed a significant amount of data demonstrating the safety and efficacy of utilizing our novel cell-based approach to improve outcomes associated with the treatment of other serious conditions. We look forward to leveraging this body of knowledge to develop a novel therapy that could lead to a safer, more effective treatment for solid tumors, preventing cancer recurrence and improving outcomes for cancer patients.”

The Role of Endothelial Cells in Regulating Cancer Cell Behavior

Endothelial cells are critical to tissue repair and health, and have a well-understood role in regulating many of the body’s healing processes, including those associated with vascular repair. Endothelial cells work as the body’s “police force” — helping maintain homeostasis and control cells under a range of pathologic stresses. The research done at MIT upon which the licensed patent portfolio is based was led by Elazer Edelman, M.D., Ph.D., Professor of Health Sciences and Technology at MIT and Professor of Medicine at Harvard Medical School, and Joseph Franses, a graduate student in the MIT Division of Health Sciences and Technology. They demonstrated that endothelial cells are a critical component of the tumor cell stroma and serve a similar role in cancer biology as they do in vascular biology, regulating cancer cell behavior, and suppressing proliferation, invasiveness and inflammation.

There is growing evidence that invasive tumor growth results from communication between cancer cells and the surrounding host cell stroma. To that end, the breakthrough MIT research, which was published today in Science Translational Medicine(1), suggests that, in the tumor setting, quiescent endothelial cells are tumor-suppressive and slow the proliferation and invasiveness of cancer cells (as studied in culture and in animals), while disruption of the endothelial cells eliminates their ability to inhibit these actions that cause metastasis. Introducing exogenous functional, healthy endothelial cells to the stromal area can restore homeostasis.

“We are highly encouraged by our initial findings, as we believe they significantly advance our understanding of the critical role endothelial cells play in inhibiting many of the aggressive aspects of cancer,” stated Dr. Edelman, who is one of the original founders of Pervasis and a current member of the company’s Board of Directors. “We believe this research will open the door to vast horizons for future research and the development of novel therapies, and we look forward to the work Pervasis is undertaking to advance these concepts to the clinical stage.”

PVS-30200 – Advantages over Current Cancer Therapies

Many current approaches to treating cancer are plagued by significant limitations such as high toxicity and serious side effects, and are systemic in nature, unable to locally target tumors. In addition, despite addressing the primary tumor, metastasis remains one of the most challenging aspects of treating cancer, and is a process that is often unpreventable and uncontrollable.

PVS-30200 utilizes Pervasis’ proprietary implantable material comprised of healthy allogeneic endothelial cells embedded in a polymer matrix that is delivered locally at the time of tumor excision to prevent cell-proliferation, inflammation and angiogenesis, key processes that lead to tumor growth and survival. The well-studied patented technology on which PVS-30200 is founded has a proven safety profile, as demonstrated by data from six clinical studies, and can be administered and targeted locally at the site of the tumor. A novel cell therapy approach, PVS-30200′s use of allogeneic cells, as opposed to autologous cells, enables “off the shelf” administration, eliminating the challenging logistical processes that are involved with the use of autologous cells.

“We plan to present our preclinical findings as well as the PVS-30200 technology to the oncology community as soon as possible; we believe this therapy has the potential to dramatically advance the promise of cell therapy as an innovative and viable treatment paradigm for cancer,” said Mr. Chereau.

Pervasis’ Current Clinical Programs

Pervasis is currently conducting a Phase 1/2 clinical study of PVS-10200, an investigational new drug under development to prevent restenosis in patients with peripheral arterial disease who undergo angioplasty and stent placement in the superficial femoral artery. The company’s most advanced program, Vascugel®, has demonstrated proof of concept and safety in two Phase 2 trials in patients undergoing arteriovenous access procedures for hemodialysis. In 2010, Pervasis announced that it had reached an agreement with the U.S. Food and Drug Administration (FDA) for its Phase 3 clinical trial of Vascugel under the FDA’s Special Protocol Assessment (SPA) procedure. Through the SPA procedure, FDA formalized its agreement that the design of the Phase 3 trial was acceptable to support a regulatory submission seeking new drug approval.

About Pervasis

Pervasis Therapeutics, Inc. is a clinical stage company developing a broad portfolio of biologically active therapeutics. Building on its deep understanding of the specialized role that the endothelium plays in regulating natural healing and repair processes associated with disease, Pervasis is advancing groundbreaking new therapies to dramatically improve the outcomes of common vascular interventions, such as arteriovenous access, angioplasties, stents, and peripheral and coronary bypass grafts — the failure of which result in serious complications and a significant increase in medical costs. The company’s most advanced program, Vascugel®, has demonstrated proof of concept and safety in two Phase 2 trials in patients undergoing vascular access for hemodialysis. In addition, Pervasis is pursuing a cell-based oncology program focused on targeting and regulating cell stroma in order to prevent key processes that play a role in advancing solid tumor growth and survival. Pervasis is also applying its platform technology to develop products in other key therapeutic areas including inflammatory disease and orthopedic injury.

Pervasis is a privately held company with funding from Flagship Ventures, Polaris Venture Partners, Highland Capital Partners and the Richter Family Fund. For more information, please visit www.pervasistx.com.

This news release contains certain forward-looking statements that involve risks and uncertainties. Such statements are only predictions and the company’s actual results may differ materially from those anticipated in these forward-looking statements. Factors that may cause such differences include the timing of clinical trials, the risk that products that appeared promising in early research and clinical trials do not demonstrate safety or efficacy in clinical trials and the risk that the company will not obtain approval to market its products.

(1) J. W. Franses, A. B. Baker, V. C. Chitalia, E. R. Edelman, Stromal Endothelial Cells Directly Influence Cancer Progression. Sci. Transl. Med. 3, 66ra5 (2011).

Company Contact:

Margaret O’Toole

Pervasis Therapeutics, Inc.

617-871-1201

motoole@pervasistx.com

Media Contact:

Liz Falcone

Feinstein Kean Healthcare

617-256-6622

liz.falcone@fkhealth.com

New study proposes blocking blood vessels to starve cancer tumors

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Posted 10 Dec 2010 — by James Street
Category Antiagiogenesis, antiangiogenesis, metastases
Friday, December 10, 2010, 16:00 [IST]

Washington, Dec 10 (ANI): Authors of a new study have stated that blocking the growth of blood vessels with antibodies could result in improved treatment of cancerous tumors.

The growth of new blood vessels from pre-existing vasculature is called angiogenesis.

In adults, angiogenesis occurs only during wound healing and menstrual cycling, but is abundant and harmful in cancerous tumors and the old-age eye disease frequently leading to blindness called age-related macular degeneration

(AMD).

Without the formation of new blood vessels, tumors cannot grow beyond a small size due to lack of oxygen and nutrients. Inhibition of angiogenesis is used in the treatment of cancer and AMD, but not all cancer patients respond, while others become refractory to therapy.

Academy professor Kari Alitalo and co-workers at the University of Helsinki, Finland, have previously shown that antibodies directed towards vascular endothelial growth factor receptor (VEGFR)-3 can inhibit lymphatic metastasis by 50-70 percent in pre-clinical tumor models.

The novel type of VEGFR-3 blocking antibody has an unprecedented mechanism of action, which was effective even at very high concentrations of the VEGF-C growth factor.

Importantly, the authors showed that combined use of antibodies blocking growth factor binding VEGFR-3 dimerization provided not only an additive, but also a synergistic inhibition.

“The new dimerization inhibitor unveils a biologically meaningful rationale for suppressing angiogenesis in tumors that could outperform traditional competitive inhibitors of angiogenesis in tumor therapy. These findings should translate into improved anti-angiogenic and anti-lymphangiogenic tumor therapies”, said Professor Alitalo. (ANI)

Protein Targeted To Stop Melanoma Tumor Growth

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Posted 10 Dec 2010 — by James Street
Category Antiagiogenesis, antiangiogenesis, metastases

Halting the growth of melanoma tumors by targeting the MIC-1 protein that promotes blood vessel development in tumors may lead to better treatment of this invasive and deadly cancer, according to Penn State College of Medicine researchers in The Foreman Foundation Research Laboratory.

“Preventing vessels from developing in tumors is one way to stop them from growing,” said lead author Gavin Robertson, Ph.D., professor of pharmacology, pathology, dermatology and surgery. “However, the identity of the proteins secreted by tumors cells enabling the angiogenesis process to occur remains to be determined.” Angiogenesis is the growth of new blood vessels from existing ones surrounding the growing tumor mass.

Tumors start as clusters of cells that transport nutrition and waste through cell walls as well as into and out of gaps between cells. This process is inefficient and provides poor nutrition to the cells in the interior of a growing tumor. As a result, the tumor mass cannot grow.

Tumor cells overcome this obstacle by secreting proteins that interact with blood vessels surrounding the tumor, causing formation of new vessels from these existing ones. The new vessels grow into the tumor to provide nutrition and remove waste. Angiogenesis leads to the formation of a fully functioning vascular structure that supplies the needed nutrition and removes cell waste, allowing tumors to grow.

By targeting the proteins that lead to angiogenesis, tumor growth can be halted. In the past, the protein VEGF was identified as a major factor in this process. However, targeting VEGF alone does not prevent tumor development in melanoma patients. The researchers looked for other proteins involved in angiogenesis and ultimately discovered MIC-1 as a regulator of this process.

The researchers reported in the American Journal of Pathology that MIC-1 is present in levels five to six times higher in 67 percent of melanoma patients compared to people without cancer.

“This suggests that the MIC-1 protein produced and secreted by these tumors might be performing an important role in the development of melanoma by controlling a key process outside of the tumor,” Robertson said.

MIC-1 stands for macrophage inhibitory cytokine-1, a member of a group of proteins that regulate cellular proliferation, migration, adhesion and immune surveillance. It was originally discovered to be associated with regulating inflammation.

By targeting MIC-1, protein levels dropped 300 to 400 percent in animal and human tissue samples, preventing blood vessel formation and decreasing tumor development by about 300 percent.

“Therapies removing MIC-1 from the blood of patients could be used to prevent tumor vessel development,” says Robertson “and as a result, the tumors would not be able to get bigger because of a lack of needed nutrition and removal of toxic cell waste products. Thus, a drug performing the job of MIC-1 removal would be an important part of a therapeutic arsenal of agents to more effectively treat melanoma.”

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