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ANG1005 Crosses The Blood-Brain Barrier To Reduce Tumor Size And Is Effective In Resistant Tumors

Angiochem, Inc. a clinical-stage biotechnology company developing drugs that are uniquely capable of crossing the blood-brain barrier to treat brain diseases, has announced that its lead drug candidate, ANG1005, has demonstrated a favorable safety and efficacy profile in more than 100 patients with brain cancer from two separate Phase 1 /2 clinical studies in patients with progressive gliomas, including recurrent glioblastoma, and in patients with progressive brain metastases. These data, which validates in humans Angiochem's peptide-based platform technology (EPiC), were presented at the Society for Neuroscience Annual Meeting in Chicago on October 18, 2009.

In the recently completed Phase 1/2 brain metastases clinical trial, greater than 70% of patients receiving therapeutic doses experienced disease control (stable disease or better) with more than half of them showing clear reduction in tumor size. Furthermore, 78% of patients with taxane resistant tumors showed responses, indicating ANG1005 has the potential to be effective against resistant tumors. Of significance, therapeutic doses of ANG1005 were present in patient brain tumor samples, indicating that the drug successfully crosses the blood-brain barrier (BBB) and concentrates in the tumor, without showing central nervous system (CNS) toxicity or immunogenicity. Similar trends in patient responses have been observed to-date in the on-going Phase 1/2 recurrent glioblastoma clinical trial with approximately 65% of patients experiencing disease control.

"It is highly encouraging to see that ANG1005 has shown the potential to be effective in metastatic brain cancers and against drug resistant tumors, that are highly aggressive and have few treatment options," commented Jan Drappatz, MD, Center for Neuro-Oncology at Dana-Farber Cancer Institute, Department of Neurology at Brigham and Women's Hospital, and, Harvard Medical School, and lead investigator for Boston-area study centers. "Furthermore, significant reductions in tumor size and reversal of neurological deficits were observed in several cases of patients with high-grade gliomas in the on-going clinical trial. We are very encouraged by these efficacy signals and look forward to learning more about the effects of ANG1005 in recurrent glioblastoma as the study progresses."

ANG1005 is a novel, next-generation taxane derivative, targeting the LRP pathway to cross the blood-brain barrier and reach therapeutic concentrations in the brain. The drug was created with Angiochem's Engineered Peptide Compound (EPiC) platform technology. Key findings to date from the clinical studies include:

  • 71% of patients (15/ 21) demonstrated disease control at therapeutic doses including seven partial responses (PR), four minor responses (MR) and four with stable disease (SD).

  • 78% of patients with taxane resistant tumors (7/9) demonstrated responses indicating ANG1005 is effective in resistant tumors, including three PRs and four MRs.

  • Similar responses were observed in metastases located in other organs such as liver, lung, lymph nodes and bone including two complete responses (CR), one in liver and one in bone.

  • Therapeutic concentrations of ANG1005 were present in patient brain tumor samples, indicating the drug successfully crosses the BBB and enters the tumor.

  • No CNS toxicity as measured by neurocognitive testing was observed.

  • No immunogenicity or antibody response was observed, even after repeated dosing.

  • Superior side-effect profile compared to other taxanes was observed based on literature references.

  • Similar trends in patient responses have been observed to date in the on-going recurrent glioblastoma trial with 65% of patients experiencing disease control.

In addition to the ANG1005 clinical findings, Angiochem's EPiC technology was also highlighted at the Neurosciences meeting. In a presentation entitled "Development of a New Engineered Peptide Compound (EPiC) Platform for the Transport of Small and Large Therapeutics to the CNS", Jean-Paul Castaigne, MD, discussed the science underlying the EPiC technology and disclosed evidence of its ability to increase the amount of a variety of different therapeutics to reach the brain, highlighting the potential neurological applications of this technology and speed at which new drugs could be developed.

"We are excited by our positive results to date with ANG1005, which strongly validate our platform technology in humans," commented Jean-Paul Castaigne, MD, MBA, President and CEO of Angiochem. "Through our peptide-based platform technology, called EPiC, Angiochem creates new chemical entities that can cross the human blood-brain barrier to reach therapeutic concentration in the brain. By harnessing naturally-occurring receptors at the surface of the BBB, our EPiC drugs have the potential to treat a variety of CNS diseases, including neurodegenerative and metabolic diseases, brain cancer, psychiatric disorders and many others."

About ANG1005 ANG1005 is a novel, next-generation taxane derivative targeting the LRP pathway. ANG1005 was engineered with the EPiC platform which was designed to cross the BBB. Studies have shown that ANG1005 gains entry into the brain compartment by targeting the low-density lipoprotein receptor-related protein (LRP) which is one of the most highly expressed receptors on the surface of the BBB. Once inside the brain, ANG1005 enters tumor cells using the same receptor-mediated pathway through LRP, which is upregulated in various cancer cells including gliomas and metastatic brain cancers.


 

 

Cotara For Treatment Of Cancer

Interim Phase II Data Presented At XIV World Congress Of Neurological Surgery Supports Potential Of Peregrine's Cotara(R) For Treatment Of Cancer

Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM) reported that clinical investigators are presenting interim Phase II data showing that its brain cancer agent Cotara(R) appeared well tolerated and demonstrated encouraging signs of efficacy in patients with glioblastoma multiforme (GBM), the deadliest form of brain cancer. The data from an ongoing Phase II study of Cotara in patients with recurrent GBM is being presented today at the XIV World Congress of Neurological Surgery Annual Meeting by Dr. Deepak Gupta, assistant professor of neurosurgery at the All India Institute of Medical Sciences (AIIMS) in New Delhi on behalf of the Cotara study team that includes Drs. A.K. Mahapatra, Ashish Suri and C.S. Bal.

Dr. Gupta will present interim data for 10 recurrent GBM patients at first relapse treated at AIIMS as part of an ongoing 40 patient Phase II clinical trial. Eight males and two females with a mean age of 51 years received a single intratumoral infusion of Cotara. Currently, follow-up duration ranges from between seven to over 73 weeks with an interim median recurrence-free survival of 33 weeks and an interim median overall survival of 41 weeks. Expected survival for patients with GBM is approximately 24 weeks from time of disease recurrence. Based on this interim data, the study authors conclude that Cotara appears to be feasible, tolerable and has encouraging signs of efficacy in recurrent GBM patients.

"This interim data from our Phase II trial suggests that Cotara has the potential to be a valuable new therapy for patients with glioblastoma, a devastating disease with few treatment options," said Dr. A.K. Mahapatra, professor of neurosurgery at AIIMS and principle investigator on the Cotara study. "Our experience to date with Cotara shows that it is feasible to administer and is quite well tolerated in these very ill patients. Most importantly, Cotara has demonstrated promising signs of efficacy. We look forward to enrolling more GBM patients in the Cotara trial over the coming months and to further assessing the experience of the patients treated to date."

The Cotara Phase ll multi-center open label study is designed to enroll up to 40 glioblastoma patients who have experienced a first relapse. The primary objective of the trial is to confirm the maximum tolerated dose of Cotara in GBM patients at first relapse. Secondary objectives include estimates of overall patient survival, progression-free survival and the proportion of patients alive at six months. Patients in the trial are receiving a single infusion of Cotara by convection-enhanced delivery (CED), a technique that delivers the agent to the tumor with great precision. Brain scans are administered at eight-week intervals post-treatment. The study is being conducted according to internationally accepted ICH and GCP guidelines.

"The interim data being presented today for the GBM patients treated at AIIMS supports the meaningful signs of clinical activity seen in prior Cotara trials as measured by median overall survival," said Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. "Previous clinical data presented earlier this year has shown the ability of Cotara to specifically deliver high doses of radiation to GBM tumors, resulting in significant anti-tumor effects. The early data from this ongoing Phase II study is providing further evidence that Cotara's ability to target tumors with great specificity may provide clinical benefit to patients with this devastating disease. We look forward to completing enrollment and reporting data on the entire trial as soon as possible."

More than 65 patients with recurrent GBM have received Cotara in the current and previous clinical studies. Localization and accumulation of the drug to the tumor have been excellent and longer-term survivors (greater than one year from the time of Cotara treatment) have been observed in all of the trials, with some recurrent GBM patients from early clinical studies now alive more than 8.5 years after treatment with Cotara. Expected survival for patients with GBM is approximately 24 weeks from time of disease recurrence.

Overall, Cotara has been administered to a total of more than 125 patients with brain, colon or liver cancer. Promising data from these studies support Cotara's ability to specifically target solid tumors and its anti-tumor activity, as well as its acceptable safety profile.

The presentation, Efficacy of Intratumoral Radioimmunotherapeutic Agent Cotara in Recurrent GBM: Initial Experience with 10 Cases, is being presented today at 2:54 pm EDT at the XIV World Congress of Neurological Surgery Annual Meeting at the Hynes Convention Center in Boston, MA.

About Cotara(R)

Cotara is an experimental treatment for brain cancer that links a radioactive isotope to a targeted monoclonal antibody designed to bind to the DNA histone complex that is exposed by dead and dying cells found at the center of solid tumors. Cotara's targeting mechanism enables it to bind to the dying tumor cells, delivering its radioactive payload to the adjacent living tumor cells and essentially destroying the tumor from the inside out, with minimal radiation exposure to healthy tissue. Cotara is delivered using convection-enhanced delivery (CED), an NIH-developed method that targets the specific tumor site in the brain. In a previous clinical study, a subset of patients with recurrent glioblastoma treated with Cotara achieved a median survival of 38 weeks, a 58% increase over the historical median survival time of 24 weeks for patients treated with standard of care therapy. In this study, 25% of 28 recurrent patients survived for more than a year post-treatment and 10% of patients survived for more than three years. These data are considered a promising development in this deadly disease. In addition to the Phase II trial now underway in India, a dosimetry and dose confirmation trial in glioblastoma patients at leading U.S. academic brain cancer centers is nearing completion. Cotara has been granted orphan drug status and fast track designation for the treatment of glioblastoma multiforme and anaplastic astrocytoma by the U.S. Food and Drug Administration.


 

New DNA Test Uses Nanotechnology to Find Early Signs of Cancer

August 17, 2009
Using tiny crystals called quantum dots, Johns Hopkins researchers have developed a highly sensitive test to look for DNA attachments that often are early warning signs of cancer. This test, which detects both the presence and the quantity of certain DNA changes, could alert people who are at risk of developing the disease and could tell doctors how well a particular cancer treatment is working.

The new test was reported in a paper called “MS-qFRET: a quantum dot-based method for analysis of DNA methylation,” published in the August issue of the journal Genome Research. The work also was presented at a conference of the American Association of Cancer Research.

“If it leads to early detection of cancer, this test could have huge clinical implications,” said Jeff Tza-Huei Wang, an associate professor of mechanical engineering whose lab team played a leading role in developing the technique. “Doctors usually have the greatest success in fighting cancer if they can treat it in its early stage.”

Wang and his students developed the test over the past three years with colleagues at the Johns Hopkins Kimmel Cancer Center. Stephen B. Baylin, deputy director of the center and a co-author of the Genome Research study, said the test represents “a very promising platform” to help doctors detect cancer at an early stage and to predict which patients are most likely to benefit from a particular therapy.

The recent study, which included the detection of DNA markers in the sputum from lung cancer patients, was designed to show that the technology was sound. Compared to current methods, the test appeared to be more sensitive and delivered results more quickly, the researchers said. “The technique looks terrific, but it still needs to be tested in many real-world scenarios,” Baylin said. “Some of these studies are already under way here. If we continue to see exciting progress, this testing method could easily be in wide use within the next five years.”

The target of this test is a biochemical change called DNA methylation, which occurs when a chemical group called methyl attaches itself to cytosine, one of the four nucleotides or base building blocks of DNA. When methylation occurs at critical gene locations, it can halt the release of proteins that suppress tumors. When this occurs, it is easier for cancer cells to form and multiply. As a result, a person whose DNA has this abnormal gene DNA methylation may have a higher risk of developing cancer.  Furthermore, these methylation changes appear to be an early event that precedes the appearance of genetic mutations, another precursor to cancer. To detect this DNA methylation, the Johns Hopkins team found a way to single out the troublesome DNA strands that have a methyl group attached to them. Through a chemical process called bisulfite conversion, all segments that lack a methyl group are transformed into another nucleotide.

Then, another lab process is used to make additional copies of the remaining target DNA strands that are linked to cancer. During this process, two molecules are attached to opposite ends of each DNA strand. One of these molecules is a protein called biotin. The other is a fluorescent dye. These partner molecules are attached to help researchers detect and count the DNA strands that are associated with cancer.

To do this, these customized DNA strands are mixed with quantum dots, which are crystals of semiconductor material whose sizes are in the range of only few nanometers across.  (A nanometer is one-billionth of a meter, far too small to see with the naked eye.).These dots are usually employed in electronic circuitry, but they have recently proved to be helpful in biological applications as well. Quantum dots are useful because they possess an important property: They easily transfer energy. When light shines on a quantum dot, the dot quickly passes this energy along to a nearby molecule, which can use the energy to emit a fluorescent glow. This behavior makes the cancer-related DNA strands light up and identify themselves.

In the Johns Hopkins cancer test, the quantum dots have been coated with a chemical that is attracted to biotin–one of the two molecules that were attached to the DNA strands. As a result, up to 60 of the targeted DNA strands can stick themselves to a single quantum dot, like arms extending from an octopus. Then, an ultraviolet light or a blue laser is aimed at the sample. The quantum dots grab this energy and immediately transfer it to the fluorescent dyes that were attached earlier to the targeted DNA strands. These dye molecules use the energy to light up.

These signals, also called fluorescence, can be detected by a machine called a spectrophotometer. By analyzing these signals, the researchers can discover not only whether the sample contains the cancer-linked DNA but how much of the DNA methylation is present. Larger amounts can be associated with a higher cancer risk.

“This kind of information could allow a patient with positive methylation to undergo more frequent cancer screening tests. This method could replace the traditionally more invasive ways for obtaining patient samples with a simple blood test,” said Vasudev J. Bailey, a biomedical engineering doctoral student from Bangalore, India, who was one of the two lead authors on the Genome Research paper. “It’s also important because these test results could possibly help a doctor determine whether a particular cancer treatment is working. It could pave the way for personalized chemotherapy.”

In addition, because different types of cancer exhibit distinctive genetic markers, the researchers say the test should be able to identify which specific cancer a patient may be at risk of developing. Markers for lung cancer, for example, are different from markers for leukemia.

Żródło:Office of News and Information,Johns Hopkins University 901 South Bond Street, Suite 540
Baltimore, Maryland 21231

 

Targeting tumors using tiny gold particles

Gold nanorods could detect, treat cancer

It has long been known that heat is an effective weapon against tumor cells. However, it's difficult to heat patients' tumors without damaging nearby tissues. Now, MIT researchers have developed tiny gold particles that can home in on tumors, and then, by absorbing energy from near-infrared light and emitting it as heat, destroy tumors with minimal side effects. Such particles, known as gold nanorods, could diagnose as well as treat tumors, says MIT graduate student Geoffrey von Maltzahn, who developed the tumor-homing particles with Sangeeta Bhatia, professor in the Harvard-MIT Division of Health Sciences and Technology (HST) and in the Department of Electrical Engineering and Computer Science, a member of the David H. Koch Institute for Integrative Cancer Research at MIT and a Howard Hughes Medical Institute Investigator. Von Maltzahn and Bhatia describe their gold nanorods in two papers recently published in Cancer Research and Advanced Materials. In March, von Maltzahn won the Lemelson-MIT Student Prize, in part for his work with the nanorods. Cancer affects about seven million people worldwide, and that number is projected to grow to 15 million by 2020. Most of those patients are treated with chemotherapy and/or radiation, which are often effective but can have debilitating side effects because it's difficult to target tumor tissue. With chemotherapy treatment, 99 percent of drugs administered typically don't reach the tumor, said von Maltzahn. In contrast, the gold nanorods can specifically focus heat on tumors. "This class of particles provides the most efficient method of specifically depositing energy in tumors," he said.

Wiping out tumors

Gold nanoparticles can absorb different frequencies of light, depending on their shape. Rod-shaped particles, such as those used by von Maltzahn and Bhatia, absorb light at near-infrared frequency; this light heats the rods but passes harmlessly through human tissue.In a study reported in the team's Cancer Research paper, tumors in mice that received an intravenous injection of nanorods plus near-infrared laser treatment disappeared within 15 days. Those mice survived for three months with no evidence of reoccurrence, until the end of the study, while mice that received no treatment or only the nanorods or laser, did not. Once the nanorods are injected, they disperse uniformly throughout the bloodstream. Bhatia's team developed a polymer coating for the particles that allows them to survive in the bloodstream longer than any other gold nanoparticles (the half-life is greater than 17 hours). In designing the particles, the researchers took advantage of the fact that blood vessels located near tumors have tiny pores just large enough for the nanorods to enter. Nanorods accumulate in the tumors, and within three days, the liver and spleen clear any that don't reach the tumor. During a single exposure to a near-infrared laser, the nanorods heat up to 70 degree Celsius, hot enough to kill tumor cells. Additionally, heating them to a lower temperature weakens tumor cells enough to enhance the effectiveness of existing chemotherapy treatments, raising the possibility of using the nanorods as a supplement to those treatments. The nanorods could also be used to kill tumor cells left behind after surgery. The nanorods can be more than 1,000 times more precise than a surgeon's scalpel, says von Maltzahn, so they could potentially remove residual cells the surgeon can't get.

Finding tumors

The nanorods' homing abilities also make them a promising tool for diagnosing tumors. After the particles are injected, they can be imaged using a technique known as Raman scattering. Any tissue that lights up, other than the liver or spleen, could harbor an invasive tumor. In the Advanced Materials paper, the researchers showed they could enhance the nanorods' imaging abilities by adding molecules that absorb near-infrared light to their surface. Because of this surface-enhanced Raman scattering, very low concentrations of nanorods - to only a few parts per trillion in water [gf1]- can be detected. Another advantage of the nanorods is that by coating them with different types of light-scattering molecules, they can be designed to simultaneously gather multiple types of information - not only whether there is a tumor, but whether it is at risk of invading other tissues, whether it's a primary or secondary tumor, or where it originated. Bhatia and von Maltzahn are looking into commercializing the technology. Before the gold nanorods can be used in humans, they must undergo clinical trials and be approved by the FDA, which von Maltzahn says will be a multi-year process. Other authors of the Advanced Materials paper are Andrea Centrone, postdoctoral associate in chemical engineering; Renuka Ramanathan, undergraduate in biological engineering; Alan Hatton, the Ralph Landau Professor of Chemical Engineering; and Michael Sailor and Ji-Ho Park of the University of California at San Diego. Park and Sailor are also authors of the Cancer Research paper, along with Amit Agrawal, former postdoctoral associate in HST; and Nanda Kishor Bandaru and Sarit Das of the Indian Institute of Technology Madras.

The research was funded by the National Institutes of Health, the Whitaker Foundation and the National Science Foundation. Nanopartz Inc. supplied gold nanoparticles, gold nanowires and the precursor gold nanorods used in this work.

A version of this article appeared in MIT Tech Talk on May 6, 2009 (download PDF).

 

Nowe kierunki badawcze w chemioterapii nowotworów OUN

New Technique May Lead To More Efficient Treatment Of Brain Cancer

Article Date: 13 Jul 2009

For patients with brain cancer, treatment options - and ultimately survival rates - are limited by the inability of most anti-cancer drugs to cross the blood-brain barrier, a natural cluster of cells that prevents toxic substances from reaching the brain.

In a study published this month by the Journal of Neuro-Oncology, a team of researchers from UNLV, Nevada Cancer Institute and University of California, Irvine reveal the effectiveness of photochemical internalization (PCI), a promising new technique that allows for targeted chemotherapeutic treatment of brain tumor cells by selectively opening the blood-brain barrier. The study, though years away from human clinical trials, is the first step toward addressing an issue that has stymied advancements in brain cancer treatment for decades.

In many cases, malignant brain tumors recur close to where they are surgically removed; 80 percent of the time they recur within a few centimeters of their site of origin.

According to Steen Madsen, UNLV Health Physics professor and one of the lead investigators on the study, current techniques to disrupt the blood-brain barrier inadvertently expose the entire brain to other potentially harmful toxins. PCI, on the other hand, allows for targeted disruption of the barrier by combining light activated drugs, or photosensitizers, with drugs known to disrupt the blood-brain barrier. This limits the flow of harmful toxins and paves the way for chemotherapy to reach the brain more efficiently.

"PCI is different than many current cancer treatment approaches in that it addresses the blood-brain barrier issue by delivering therapeutic agents to targeted areas of the brain," said Madsen. "This targeted delivery could make PCI potentially useful as a treatment not only for brain cancer but for a variety of neurological conditions, such as Alzheimer's and Parkinson's diseases."

In PCI, photosensitizers are injected into the patient. This is followed by an injection of a drug known to disrupt the blood-brain barrier. The photosensitizers surround the drug molecules and prevent them from infiltrating the entire brain. Then, a specific wavelength of light therapy is focused on the target area, activating the photosensitizers and releasing the barrier-busting molecules. With the barrier now selectively, yet temporarily, opened, chemotherapy can be administered to the targeted areas.

To test the effectiveness of chemotherapy treatment combined with PCI, researchers used rats segmented into three groups; one receiving PCI and chemotherapy, one receiving traditional chemotherapy treatment without PCI, and one receiving no treatment. Of the group administered PCI and chemotherapy, more than 60 percent survived more than 70 days, far surpassing either of the other two groups. The findings suggest that, under the appropriate conditions, PCI is a promising method to selectively disrupt the blood-brain barrier for treatment.

Researchers note that while PCI-aided delivery of chemotherapy to the brain has proven effective in laboratory tests, additional testing prior to human clinical trials is needed to identify other less-toxic blood-brain barrier agents to be used in tandem with the photosensitizer in the PCI process.

The study was funded through the Nevada Cancer Institute's Collaborative Grant Program Participating in the study with Madsen were Henry Hirschberg, UNLV health physics adjunct professor and research professor with the University of California, Irvine's Beckman Laser Institute; UNLV graduate researchers Michelle Zhang and David Chighvinadze; Michael Gach from Nevada Cancer Institute; Francisco Uzal from the University of California, Davis; Qian Peng from the Norwegian Radium Hospital; and Chung Ho-Sun of the University of California, Irvine.

Source University of Nevada