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GenSpera’s Targeted “Death Carrot” Toxin in Trials for Two Cancers

XCONOMY

Top Stories in Texas

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GenSpera’s Targeted “Death Carrot” Toxin in Trials for Two Cancers

http://www.xconomy.com/texas/2014/03/27/gensperas-targeted-death-carrot-toxin-in-trials-for-two-cancers/

Bernadette Tansey 3/27/14

 

Craig Dionne has a record of experience in drug development and a lot of friends in the pharmaceutical industry. But when his friends first heard about the experimental drug he started working on some years ago, he says their initial reaction was alarm—to put it mildly.

“They told me I was a fool,” Dionne says affably. Dionne is CEO of San Antonio, TX-based GenSpera, which has now started a second round of early stage clinical trials on the experimental drug he took a chance on. He’s hoping the trials are about to show his friends he was right.

Back in the early 1990s, Dionne and his collaborators at Johns Hopkins University saw potential for a cancer drug in a highly potent toxin, thapsigargin, found in a common Mediterranean weed called Thapsia Garganica. You’ll find it described as the “death carrot’’ in online accounts.

Thapsigargin kills fast-growing cells. So far, so good; that’s a routine property of chemotherapy drugs. But the relative safety of classical chemotherapy agents rests on the fact that they’re more destructive to rapidly multiplying tumor cells than they are to slow-growing normal cells.

Thapsigargin doesn’t work that way—which initially made it alarming to Dionne’s friends. It’s an equal opportunity cell-killer.

“It can kill cells that grow slowly,” Dionne says. That makes it a threat to normal cells, unless a drug company can successfully tweak it. And Dionne saw a reason to try.

Like most normal cells, some cancer cells also grow slowly, such as those in tumors of the prostate. And such cancer cells can resist chemotherapy drugs that target fast-growing cells. Dionne and his collaborators at Johns Hopkins reasoned that thapsigargin might be an effective weapon against slow-growing tumor cells, if it could be modified to spare normal cells. The end result of their chemical tinkering is GenSpera’s experimental drug G-202, which has now moved into a second round of early stage clinical trials.

The compound was designed to allow the powerful toxin to move through the bloodstream in an inactive form until it’s released by an enzyme, PSMA, found at higher levels on the surface of certain tumor cells, Dionne says. He compares G-202 to a grenade with a pin ready to be pulled.

A molecule of G-202 contains a modified form of thapsigargin called 12ADT, which is linked to a small peptide. The effect of that peptide—a small chain of five amino acids—is to keep 12ADT soluble in the watery environment of the blood. More importantly, he peptide keeps the toxin inactive.

But when G-202 encounters a cell with the enzyme PSMA (prostate-specific membrane antigen) on its surface, the enzyme clips the peptide off the toxic 12ADT molecule. The toxin, now insoluble in water but highly soluble in fats, can sink through the lipid-rich outer membrane of a nearby cancer cell and start its deadly work.

Dionne says G-202 is similar to the new class of targeted cancer drugs called antibody-drug conjugates, which are also designed to deliver a toxin only to particular tumor cells. These drugs combine a toxin with an antibody engineered to bind to a specific molecule on the surface of a cancer cell. However, antibodies are large proteins whose unique amino acid sequences and folding patterns can help them fit selectively only with certain cell surface receptors.

Serotonin-producing cells develop early on in the ENS, and if this buy generic levitra development is affected, the second brain cannot form properly. You will be helped to prolong your erection in a more healthy levitra online devensec.com and natural way by this medicine. Sexual dysfunction is a common concern shared by many women. generic levitra cheap This levitra 20mg canada medicine may lead to allergic reaction in some individuals. By contrast, G-202‘s targeting agent, the small peptide, could theoretically be clipped away from its toxic payload by enzymes other than PSMA, Dionne says. If that happened, the toxin could be released in the vicinity of normal cells rather than tumor cells. This is one of the reasons why GenSpera has spent years on preclinical testing and animal studies before launching its first clinical trial of G-202 in humans in 2011, he says.

Dionne says the company also took a close look at the cardiovascular effects of the experimental drug because of its molecular mechanism of action. Thapsigargin works by disrupting a molecular pump that regulates the level of calcium ions inside cells—and ion exchanges are central to the functioning of the cardiovascular system, Dionne says. Once inside any cell, whether a tumor cell or a normal one, thapsigargin causes a damaging influx of calcium, which starts a process of programmed cell death called apoptosis.

GenSpera also had to watch out for off-target effects of G-202 for another reason. Although the target enzyme PSMA appears in a higher concentration on cells of the prostate than on many other cells, it has been found as well in certain normal tissues, such as sections of the brain, small intestine, and kidney. Dionne says G-202 can’t pass through the blood-brain barrier. Studies of the drug’s action in animals and in humans so far have not turned up significant damage to the other normal cells bearing the PSMA enzyme, he added.

However, the discovery of enriched PSMA levels in yet another type of tissue has expanded the possible uses of G-202. The enzyme is more abundant on the cells of blood vessels that bring nutrients and oxygen to solid tumors than it is in normal blood vessels. Based on this finding, GenSpera began widening its views beyond prostate cancer, Dionne says. If the toxin in G-202 could be released by PSMA in tumor blood vessels, these vessels might disintegrate, and the tumor might starve and die.

“The potential applications are so much broader,” Dionne says.

In GenSpera’s first small trials in 2011 and 2012, 44 participants with a range of different cancer types received doses of G-202. Dionne says the drug appeared to have no serious effects on the liver, cardiovascular system, or bone marrow. Kidney damage could be prevented by limiting the G-202 dose and giving trial participants plenty of water, he says.

Although the main goal of the first trial was to assess the safety of G-202, GenSpera noted that a few trial participants with advanced liver cancer survived longer than expected. Encouraged by those signs, GenSpera is now conducting a Phase II trial in up to 17 adults with advanced hepatocellular carcinoma who are no longer helped by sorafenib (Nexavar), a cancer drug co-owned by Bayer and Amgen.

In March, GenSpera also began a Phase II trial in up to 34 participants with the brain cancer glioblastoma multiforme at the University of California San Diego’s Moores Cancer Center. The company may also conduct trials in prostate and kidney cancer if it can raise the funding.

GenSpera (OTC: GNSZ) is a tiny virtual company, that had $3.6 million in cash at the end of 2013—enough to fund its operations through at least nine months of this year. The company last week announced a share offering to raise as much as $7.5 million.

Dionne, a former executive at Cephalon, which was acquired by Teva Pharmaceutical Industries (NASDAQ: TEVA) in 2011, co-founded GenSpera in 2003. The firm began its preclinical studies in 2007, when it raised its first funds from outside investors. Dionne, who is GenSpera’s chief financial officer as well as CEO, is one of the company’s staff of two full-time employees. GenSpera contracts out all its other work.

“We’re virtual out of choice,” he says.

GenSpera’s scientific advisory board includes company co-founders John Isaacs and Samuel Denmeade, who are oncology professors at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.

GenSpera has raised $24.3 million since its inception, and the majority has come from high net worth individuals who often continue to reinvest, Dionne says. The company went public in 2009 and trades in the OTCQB tier of the Over-The-Counter Markets Group. GenSpera’s market capitalization is about $37 million.

Dionne says the company’s ideal plan is to seek a pharmaceutical company partner or buyer after conducting Phase II trials that show the potential of G-202 in solid tumors.

“We want to be valued across a range of tumor types,” Dionne says. The company has been built with the goal of making it attractive to big drug companies, he says.

“Our customer is large pharma,” Dionne says. “That’s who is ultimately going to pay us what we’re worth.”

G-202 Represents Novel Approach for Attacking Advanced HCC

G-202 Represents Novel Approach for Attacking Advanced HCC

http://www.onclive.com/publications/oncology-live/2014/march-2014/g-202-represents-novel-approach-for-attacking-advanced-hcc/2

Devalingam Mahalingam, MD, PhD

Published Online: Monday, March 24, 2014

Prodrug chemotherapy is an exciting approach by which higher concentrations of cytotoxic or biologically active agents can be achieved at a tumor site while avoiding the systemic toxicity of a non-cell-specific toxin. One promising example of this strategy is the development of the cytotoxic agent thapsigargin, which is derived from the Thapsia garganica plant once known in Mediterranean cultures as the “death carrot.” Efforts to engineer this agent into an effective therapy for hepatocellular carcinoma (HCC) are advancing.

Thapsigargin can kill a broad spectrum of cancer cells but with detrimental effects on normal endothelial cells, fibroblasts, and osteoblasts. The molecular mechanism of action is attributed to the induction of apoptosis (cell death) by a pronounced increase in cytosolic calcium due to blockade of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump to which thapsigargin binds with high affinity.

Due to the highly toxic characteristics of thapsigargin, the challenge was how to deliver the agent to tumors while causing the least impact on normal cells and tissue. The answer was to develop a relatively nontoxic form of thapsigargin; that is, the prodrug, which can be converted into the active cytotoxic agent at a particular location, specifically at the tumor site, for effective anticancer treatment.

In this pursuit, G-202 was generated by coupling a prostate-specific membrane antigen (PSMA)-specific peptide to an analogue of the potent thapsigargin. The daunting task was to identify a tumor-specific protein from which an appropriate peptide could be linked to the drug and make the drug inactive until the peptide could be cleaved from the drug only at the tumor site by that specific protein, such as PSMA, a glutamate carboxypeptidase type II enzyme that cleaves the acidic amino acids glutamate and aspartate. PSMA was of interest because of its unique presence in prostate cancer and most tumor endothelial cells, but not in normal vasculature or normal tissue epithelium. Of note, PSMA is also found in the vasculature of 90% of HCC tumors.

This is the best option as find this pharmacy shop now buy generic levitra you like and get enjoyed. With that formula, the science has cialis line order invented a new kind of medicine that is called generic medicine. There are many women who think whether they will ever regain their penile strength back or price viagra not. It is seriously advised by most doctors to seek for ay help purchase viagra online you could try here when you meet this certain sexual problems. The immense promise of G-202 as a future practice- changing therapy is apparent because this compound has biologic activity only after proteolytic cleavage by PSMA occurs at the tumor site. Normal healthy cells are no more susceptible to unwanted cytotoxic activity because thapsigargin is blocked by the masking peptide, which is selectively cleaved by PSMA in PSMA-positive human tumors such as prostate and HCC tumors. Within the neovasculature, the nontoxic prodrug G-202 is converted by hydrolysis into the active cytotoxic analogue of thapsigargin, 12ADT-Asp, which has the ability to trigger apoptosis by a mechanism similar to that of thapsigargin. Compared with thapsigargin alone, G-202 can achieve higher concentrations of the active agent at the tumor site while avoiding systemic toxicity.

When tested against a panel of human cancer xenografts in vivo, G-202 produced substantial tumor regression at doses that were minimally toxic to the host. These encouraging results led to a phase I open-label, single-arm, dose-escalation study in patients with advanced cancer. The study was designed to evaluate the safety and pharmacokinetics of G-202 as well as to identify a phase II dosing regimen. GenSpera, Inc, based in San Antonio, is sponsoring the research.

In all, 44 patients were recruited for the study at three US institutions, including the Cancer Therapy & Research Center at UT Health Science Center in San Antonio, which was the lead patient enrollment site. Of the participants, 28 were included in the dose-escalation portion of the study and 16 were part of an expanded cohort. Results were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.1

 

Most of the toxicities reported were mild and of grade 1 severity, with some patients experiencing increased creatinine/acute kidney injury/acute renal failure, nausea, and infusion-related reaction, ameliorated by prophylactic IV hydration, IV antiemetics, and steroid administration on the day of infusion. Five patients with HCC were enrolled in the expansion cohort. This group averaged 6 cycles of treatment per patient (range, 2-12 cycles), for a total of 29 cycles among all patients. An encouraging outcome was the observation of stable disease for more than 9 cycles in each of 2 patients.

This has led to the opening of a multicenter phase II study evaluating G-202 as second-line therapy for patients with HCC after treatment failure with sorafenib (Nexavar).2 If the early clinical finding holds true in controlling progression of HCC with minimal toxicity to patients, and a successful clinical development program is completed, G-202 could one day become a treatment option for patients with advanced HCC.

New therapies are urgently needed for this patient population. HCC ranks third in cancer deaths worldwide, with ~360,000 deaths annually. The majority (75%) of the world’s patients with HCC are in Asia-Pacific Rim countries. In the United States, the incidence of HCC is increasing and has risen at a faster rate in the Latino/Hispanic population than among non-Hispanic whites. Currently, the only FDA-approved drug for HCC is sorafenib, which gained an indication for unresectable HCC in 2007 after clinical trial findings demonstrated a 3-month improvement in overall survival versus placebo.
– See more at: http://www.onclive.com/publications/oncology-live/2014/march-2014/g-202-represents-novel-approach-for-attacking-advanced-hcc/2#sthash.TX7mxRWe.dpuf

 

GenSpera registers for public offering

 

 

Mar 21, 2014, 1:15pm CDT

GenSpera registers for public offering

http://www.bizjournals.com/sanantonio/blog/2014/03/genspera-registers-for-public-offering.html

Biotech firm GenSpera has filed with the SEC for a future public offering.

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W. Scott Bailey

GenSpera Inc. has filed a registration with the U.S. Securities and Exchange Commission for a public offering.

The filing does not specify how many shares of stock the San Antonio-based biotech company plans to offer or at what price.

It does indicate that GenSpera (GNSZ: OTC) intends to use the proceeds from the sale of stock to fund Phase II clinical trials of its lead drug G-202 in patients with liver and brain cancer. The company also plans to dedicate a portion of those proceeds for working capital.

GenSpera, which is still in the research-and-development phase for its lead drug, reported a net loss of $2 million in the fourth quarter of 2013.

On Tuesday, I reported that GenSpera has launched a Phase II clinical trial for G-202 with patients who have glioblastoma multiforme, the most prevalent type of primary brain cancer. The trial will be conducted at the University of California at San Diego’s Moores Cancer Center.

GenSpera enrolls brain cancer mid-stage trial with ‘grenade’ delivery

GenSpera enrolls brain cancer mid-stage trial with ‘grenade’ delivery

Blood-brain barrier in glioblastoma? ‘We don’t need to worry about it.’

http://www.fiercedrugdelivery.com/search/site/genspera

The weed Thapsia garganica, which provides the active ingredient thapsigargin for G-202–Courtesy of GenSpera

March 19, 2014 | By Michael Gibney

Texas cancer drug delivery specialist GenSpera is enrolling a new study for its molecular “grenade” candidate G-202. This time it’s a Phase II for the treatment of the notoriously aggressive brain cancer glioblastoma.

The G-202 candidate in question is the same as one that garnered GenSpera positive results in a Phase I study ending in October last year. That trial aimed at solid tumors with a subset of patients with hepatocellular carcinoma, a type of liver cancer.

Along with a research team at the University of California in San Diego, GenSpera will conduct the new study in two stages in up to 34 patients with recurrent forms of glioblastoma who have already undergone at least one major treatment–surgery or radiation. The drug is designed to be delivered via intravenous infusion for about an hour over the course of three days.

As an endpoint, GenSpera is looking for patients to be progression-free at 6 months. Historically, GenSpera CEO Craig Dionne told FierceDrugDelivery, about 15% of glioblastoma patients are progression-free by this point, and GenSpera is aiming to boost that number to 30%.
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G-202 has shown to be effective before. But there are many delivery challenges that come with getting drugs past the blood-brain barrier, and here’s where GenSpera’s drug could have an edge: it doesn’t need to cross the barrier and its drugs work from within the blood vessels in the tumor.

Since G-202 is designed to act on the blood vessels inside a tumor, constricting them so as to starve the tumor, Dionne said, it doesn’t come up against the same challenges as other drugs that need to cross the endothelial cells to get into the tumor’s mainframe.

“Our approach to the blood-brain barrier,” Dionne said, “is we don’t need to worry about it.”

Dionne compares G-202’s release mechanism to a “grenade” complete with a “pin” that’s pulled at a specific site in a tumor’s blood vessel. G-202 is the first to take advantage of the enzymatic action of the prostate-specific membrane antigen, PSMA, that exists in abundance at tumors such as glioblastoma. The PSMA enzyme pulls off a peptide cap on the drug that delivers a hefty dose of the specifically deadly toxin 12ADT.

“If you look at glioblastoma, it is highly vascularized and makes a lot of PSMA, which is perfect for us,” Dionne said. “The toxin is targeted with the antibody drug conjugate and, taking advantage of the enzymatic action, it delivers thousands of active molecules. The amplification is a huge part.”

The toxin 12ADT is the final component of the uniquely designed drug. Its active ingredient, thapsigargin, is derived from a Mediterranean wild weed called Thapsia garganica, Dionne said, which works by disrupting a pump that regulates calcium levels in the blood vessel cells. The toxin is extremely potent, more so even than common cancer drugs such as doxorubicin, and kills independently of cell division rate, which means it can affect slow-growing tumors or even cancer stem cells that can linger after a tumor is mostly eradicated. According to Dionne, once the toxin is released, it is highly lipophilic and stays there in the tumor.

GenSpera’s other Phase II trial for G-202 in hepatocellular carcinoma is also currently being enrolled, Dionne said, with 16 patients on board.

– here’s the release