[Rich66]

Cancer Res. 2007 Apr 15;67(8):3560-4.
Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors.

Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS.
Department of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada.
Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide. Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy.

PMID: 17440065 [PubMed - indexed for MEDLINE]


Public release date: 22-Jul-2010
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http://www.eurekalert.org/pub_releas...-isc072210.php

Contact: Kim Irwin
kirwin@mednet.ucla.edu
310-206-2805
University of California - Los Angeles
Irradiating stem cell niche doubles survival in brain cancer patients

Patients with deadly glioblastomas who received high doses of radiation that hit a portion of the brain that harbors neural stem cells had double the progression-free survival time as patients who had lower doses or no radiation targeting the area, a study from the Radiation Oncology Department at UCLA's Jonsson Comprehensive Cancer Center has found.
Patients who underwent high doses of radiation that hit the specific neural stem cell site, known as the stem cell niche, experienced 15 months of progression-free survival, while patients receiving lower or no doses to this region experienced 7.2 months of progression-free survival, said Dr. Frank Pajonk, an associate professor of radiation oncology, a cancer center researcher and senior author of the study.
Pajonk said the study, published today in the early online edition of the journal BMC Cancer, could result in changes in the way radiation therapy is given to patients with these deadly brain cancers.
"Our study found that if you irradiated a part of the brain that was not necessarily part of the tumor the patients did better," Pajonk said. "We have been struggling for years to come up with new combinations of drugs and targeted therapies that would improve survival for patients with glioblastoma. It may be that by re-shaping our radiation techniques we can extend survival for these patients."
The retrospective study focused on the cases of 55 adult patients with grade 3 or grade 4 glioblastomas who received radiation at UCLA between February 2003 and May 2009. Pajonk said a prospective study is needed to confirm the results.
There is some evidence that many if not all cancers may spring from stem cells or progenitor cells that normally repair damage to the body, but that somehow become mutated and transform into cancer. In this case, Pajonk said the neural stem cell niche, called the periventricular region of the brain, may also be harboring stem cells that have transformed into brain cancer stem cells. However, the niche serves as a sort of safe harbor for the cancer stem cells, keeping them away from the site of the tumor but able to re-grow it once it's removed and the malignant areas of the brain have been treated.
Pajonk theorizes that the brain cancer stem cells in the patients whose niches were irradiated with higher doses may have been damaged or eliminated, giving these patients more time before their cancer recurred.
"This suggests that the neural stem cell niche in the brain may be harboring cancer stem cells, thus providing novel therapy targets," the study states. "We hypothesize that higher radiation doses to these niches improve patient survival by eradicating the cancer stem cells."
Glioblastomas are the deadliest form of brain cancer. Surgery, chemotherapy and radiation are not usually effective and life expectancy is about 12 to 18 months. New and more effective treatments are needed to help this patient population, Pajonk said.
The radiation therapy could damage neural stem cells as well as the cancer stem cells, Pajonk said, but those may be replaceable at some future date using induced pluripotent stem cells made from the patient's own cells. The induced pluripotent stem cells, which like embryonic stem cells can make every cell in the body, could be induced into becoming neural stem cells to replace those damaged or eradicated by the radiation to the niche.





Cancer Chemother Pharmacol. 2010 Jan 28. [Epub ahead of print]
Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors.

Morgan RJ, Synold T, Mamelak A, Lim D, Al-Kadhimi Z, Twardowski P, Leong L, Chow W, Margolin K, Shibata S, Somlo G, Yen Y, Frankel P, Doroshow JH.
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA, rmorgan@coh.org.
PURPOSE: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. METHODS: Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m(2)/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks. RESULTS: Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m(2)/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs. CONCLUSIONS: The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m(2)/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.

PMID: 20107803 [PubMed - as supplied by publisher]







http://www.modernmedicine.com/modern...tegoryId=40137

Breast Cancer Metastasis Gene Linked to Poor Survival

High expression of HK2 found in brain metastases compared with primary tumors Sep 3, 2009 THURSDAY, Sept. 3 (HealthDay News) -- Expression of a gene involved in glucose metabolism and cell death is higher in breast cancer brain metastases compared with primary tumors, and high expression is associated with poor survival, according to a study published online Sept. 1 in Molecular Cancer Research. Diane Palmieri, Ph.D., from the National Cancer Institute in Bethesda, Md., and colleagues compared global gene expression by microarray in eight brain metastases of breast tumors and nine unlinked primary breast tumors matched for histology, tumor-node-metastasis stage, and hormone receptor status. The researchers found that the expression of four genes was significantly reduced in brain metastases, while the expression of another was increased. In particular, the expression of hexokinase 2 (HK2), which is important in glucose metabolism and apoptosis, was higher in the brain metastases, and blocking expression reduced cell growth when glucose was limiting. Increased HK2 expression in a separate group of 123 breast cancer brain metastases was significantly associated with poor survival after craniotomy. "The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target," Palmieri and colleagues conclude. Abstract Full Text (subscription or payment may be required)

Can we protect the brain against tumor metastasis?

Posted on June 15, 2009 by speakingofresearch

http://speakingofresearch.com/2009/0...or-metastasis/

The tumor cells bind to a blood vessel structure called the vascular basement membrane (VBM), but what the Oxford scientists really wanted to know was what caused the tumor cells to bind to the VBM. Once again using mice with cranial windows fitted they found that an enzyme named focal adhesion kinase was highly active where the tumor cells were interacting with the VBM. Focal adhesion kinase is part of a pathway through which a class of proteins known as the integrins control the interaction between many cells and either other cells or extracellular proteins such as the components of the vascular basement membrane, an observation which suggested that an integrin plays a key role in the binding of tumor cells to the VBM. They next found that a particular integrin named Beta 1 integrin is present on all the tumor cell lines they were studying, and that antibodies blocking it could prevent the tumor cells from binding components of the VBM in vitro and to blood vessels in human brain tissue slices.
But would the anti-Beta 1 integrin blocking antibody prevent tumor metastasis in living animals? The answer was yes, the antibodies greatly reduced the growth tumors from human breast tumor cells that were injected directly into the brains of mice. To further emphasize the importance of Beta 1 integrin in brain metastasis they found that when mouse lymphoma cells that had been genetically engineered to lack Beta 1 integrin were injected into mouse brains they formed far smaller tumors than non-GM lymphoma cells.

1) Carbonell W.S. et al. “The vascular basement membrane as “soil” in brain metastasis.” PLoS ONE Volume 4(6):e5857 (2009) DOI:10.1371/journal.pone.0005857
2) Park C.C. et al. “Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo.”Cancer Res. Volume 66(3), Pages 1526-1535 (2006) DOI:10.1158/0008-5472.CAN-05-3071



New Scientific Publication Highlights Long-Term Survival of Brain Cancer Patients Treated With Peregrine Pharmaceuticals' Cotara(R)


-Article in Current Cancer Therapy Reviews Reports on GBM Patients Who Have Survived More than Nine Years after Treatment with Cotara-


TUSTIN, Calif., Feb. 11 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (PPHM) today reported publication of data in the online edition of the journal Current Cancer Therapy Reviews that supports the clinical potential of the company's novel brain cancer agent Cotara® for the treatment of patients with glioblastoma multiforme (GBM), the deadliest form of brain cancer.(1) Cotara specifically targets cells at the center of brain tumors, so its radioactive payload is able to kill cancer cells while leaving healthy tissue largely unaffected. Cotara is currently being tested in a Phase II clinical trial in recurrent GBM patients.
The new data from investigators at the Huntsman Cancer Institute at the University of Utah Medical Center and researchers at Peregrine Pharmaceuticals reports on long-term patient follow-up from an earlier Phase I trial in 28 GBM patients with recurrent disease. Data presented from the study showed that seven of 28, or 25% of the patients survived more than one year after treatment and three of the 28, or 10.7% of the GBM patients treated in this study have survived more than five years after treatment, including two patients who have survived more than nine years, a positive finding compared to the 3.4% five-year survival rate from initial diagnosis reported by the U.S. Brain Tumor Registry. Additionally, the median survival time of the 28 patients was 38 weeks, a 58% increase over the historical median survival time of 24 weeks for GBM patients treated with standard-of-care therapy.
"The positive results seen in this trial suggest that Cotara has the potential to be a valuable new therapy for patients with glioblastoma, a devastating disease with few treatment options," said lead author Randy L. Jensen, M.D., Ph.D., a researcher at the Huntsman Cancer Institute and associate professor, Department of Neurosurgery at the University of Utah Medical Center. "Our experience with GBM patients treated with Cotara in this trial showed that it demonstrated superior median overall survival compared to historical data, and resulted in long-term survival for a number of patients, a rare occurrence in this deadly disease. These promising data highlight the importance of completing the current clinical trials to confirm these results and of advancing this promising agent towards possible regulatory approval."
Cotara is currently being studied in a Phase II clinical trial for the treatment of GBM in patients who have experienced a first relapse. Interim data from this study was presented at the XIV World Congress of Neurological Surgery in September 2009. It highlighted 10 GBM patients treated at one of the clinical sites and included follow-up durations ranging from seven weeks to over 73 weeks, showing an interim median recurrence-free survival of 33 weeks and an interim median overall survival of 41 weeks. Patient enrollment in this trial has now passed the half way mark. Patient enrollment was recently completed in a Cotara dosimetry and dose confirmation trial in recurrent GBM patients. Data from this study presented at the Society of Nuclear Medicine 2009 Annual Meeting showed that Cotara appeared to be safe and well tolerated, strongly concentrating in the brain tumor while leaving other organs largely unaffected. A number of patients in this trial have surpassed the median expected survival time for relapsed GBM patients. Patient follow-up is continuing.
"The new data published today reinforces and updates the encouraging results we have reported from all three trials of Cotara in GBM patients," noted Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. "Data from the two current Cotara trials presented at medical conferences last year has shown encouraging signs of efficacy and confirmed the ability of Cotara to specifically deliver high doses of radiation to GBM tumors, resulting in significant anti-tumor effects. We look forward to completing the ongoing trials while we assess a variety of clinical and regulatory options to make Cotara more widely available to patients with this devastating disease."
Senior author Missag H. Parseghian, Ph.D., senior director of research and development at Peregrine added, "In total, 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."
Overall, Cotara has been administered to a total of 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.
(1) Current Cancer Therapy Reviews, (February) 2010, Clinical Update: Treatment of Glioblastoma Multiforme with Radiolabeled Antibodies that Target Tumor Necrosis, pp.13-18 (6) Authors: Randy L. Jensen, Joseph S. Shan, Bruce D. Freimark, Debra A. Harris, Steven W. King, Jennifer Lai, Missag H. Parseghian
About Cotara®
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. 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.



Br J Cancer. 2010 Feb 16;102(4):685-92. Epub 2010 Jan 12.
In vivo effects of rosiglitazone in a human neuroblastoma xenograft.

Cellai I, Petrangolini G, Tortoreto M, Pratesi G, Luciani P, Deledda C, Benvenuti S, Ricordati C, Gelmini S, Ceni E, Galli A, Balzi M, Faraoni P, Serio M, Peri A.
Correspondence: Professor A Peri, E-mail: a.peri@dfc.unifi.it
Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, 50139 Florence, Italy.
Background:Neuroblastoma (NB) is the most common extra-cranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. There is in vitro evidence that the peroxisome proliferator-activated receptor gamma (PPARgamma) might be a target for pharmacological intervention in NB. We have previously demonstrated that the PPARgamma agonist rosiglitazone (RGZ) exerts strong anti-tumoural effects in the human NB cell line, SK-N-AS. The aim of this study was to evaluate whether RGZ maintains its anti-tumoural effects against SK-N-AS NB cells in vivo.Methods and results:For this purpose, tumour cells were subcutaneously implanted in nude mice, and RGZ (150 mg kg(-1)) was administered by gavage daily for 4 weeks. At the end of treatment, a significant tumour weight inhibition (70%) was observed in RGZ-treated mice compared with control mice. The inhibition of tumour growth was supported by a strong anti-angiogenic activity, as assessed by CD-31 immunostaining in tumour samples. The number of apoptotic cells, as determined by cleaved caspase-3 immunostaining, seemed lower in RGZ-treated animals at the end of the treatment period than in control mice, likely because of the large tumour size observed in the latter group.Conclusions:To our knowledge, this is the first demonstration that RGZ effectively inhibits tumour growth in a human NB xenograft and our results suggest that PPARgamma agonists may have a role in anti-tumoural strategies against NB.

PMID: 20068562 [PubMed - in process]



Br J Cancer. 2009 Mar 24;100(6):894-900. Epub 2009 Feb 24.
Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients.

Park YH, Park MJ, Ji SH, Yi SY, Lim DH, Nam DH, Lee JI, Park W, Choi DH, Huh SJ, Ahn JS, Kang WK, Park K, Im YH.
Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM.

PMID: 19240719 [PubMed - indexed for MEDLINE]











Cancer Biol Ther. 2009 Oct;8(20):1924-33. Epub 2009 Oct 12.
Modulation of KCa channels increases anticancer drug delivery to brain tumors and prolongs survival in xenograft model.

Ningaraj NS, Sankpal UT, Khaitan D, Meister EA, Vats TS.
Memorial Health University Medical Center, Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Hoskins Center for Biomedical Research, Savannah, GA, USA. ningana1@memorialhealth.com
Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to brain tumors. Previously we have shown that potassium channel agonists increased carboplatin and Her-2 neu antibody delivery in animal glioma models. Here, we studied whether potassium channel agonist increase TMZ and Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial tumor. The K(Ca) channel activity and expression was also evaluated in human glioma tissues. We administered NS-1619, calcium-dependent potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and Herceptin do not cross the BTB in significant amounts, however, NS-1619 co-infusion with [(14)C]-TMZ and Herceptin resulted in enhanced drug delivery to brain-tumor cells. The combination treatment of TMZ and Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit brain tumor patients by increasing anti-neoplastic agent's delivery to brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit brain tumor patients.

PMID: 19738431 [PubMed - in process]


PLoS One. 2009 Dec 15;4(12):e8314.
Neural stem cells as a novel platform for tumor-specific delivery of therapeutic antibodies.

Frank RT, Edmiston M, Kendall SE, Najbauer J, Cheung CW, Kassa T, Metz MZ, Kim SU, Glackin CA, Wu AM, Yazaki PJ, Aboody KS.
Division of Hematology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA. rikfrank@gmail.com
BACKGROUND: Recombinant monoclonal antibodies have emerged as important tools for cancer therapy. Despite the promise shown by antibody-based therapies, the large molecular size of antibodies limits their ability to efficiently penetrate solid tumors and precludes efficient crossing of the blood-brain-barrier into the central nervous system (CNS). Consequently, poorly vascularized solid tumors and CNS metastases cannot be effectively treated by intravenously-injected antibodies. The inherent tumor-tropic properties of human neural stem cells (NSCs) can potentially be harnessed to overcome these obstacles and significantly improve cancer immunotherapy. Intravenously-delivered NSCs preferentially migrate to primary and metastatic tumor sites within and outside the CNS. Therefore, we hypothesized that NSCs could serve as an ideal cellular delivery platform for targeting antibodies to malignant tumors. METHODS AND FINDINGS: As proof-of-concept, we selected Herceptin (trastuzumab), a monoclonal antibody widely used to treat HER2-overexpressing breast cancer. HER2 overexpression in breast cancer is highly correlated with CNS metastases, which are inaccessible to trastuzumab therapy. Therefore, NSC-mediated delivery of trastuzumab may improve its therapeutic efficacy. Here we report, for the first time, that human NSCs can be genetically modified to secrete anti-HER2 immunoglobulin molecules. These NSC-secreted antibodies assemble properly, possess tumor cell-binding affinity and specificity, and can effectively inhibit the proliferation of HER2-overexpressing breast cancer cells in vitro. We also demonstrate that immunoglobulin-secreting NSCs exhibit preferential tropism to tumor cells in vivo, and can deliver antibodies to human breast cancer xenografts in mice. CONCLUSIONS: Taken together, these results suggest that NSCs modified to secrete HER2-targeting antibodies constitute a promising novel platform for targeted cancer immunotherapy. Specifically, this NSC-mediated antibody delivery system has the potential to significantly improve clinical outcome for patients with HER2-overexpressing breast cancer.

PMID: 20016813 [PubMed - in process]



Drug now used to treat erectile dysfuncton may enhance delivery of herceptin to certain brain tumors
LINK

LOS ANGELES (May 7, 2010) -- New research by scientists at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute suggests that a drug currently approved to treat erectile dysfunction may significantly enhance the delivery of the anti-cancer drug Herceptin to certain hard-to-treat brain tumors. The research, published in the journal PLoS ONE, could help doctors improve treatments for lung and breast cancers that have metastasized to the brain.
While cancers that originate in the brain are relatively rare -- approximately 22,000 patients are diagnosed with a primary brain tumor every year -- nearly 10 times that many people develop brain tumors from cancers that began elsewhere in the body. Lung cancer remains the leading cause of cancer death in the U.S., and about 20 percent of lung cancers metastasize to the brain. Breast cancer and melanoma may also spread to the brain, and once this happens, the cancer becomes extremely difficult to treat and the prognosis turns poor.
Even if a cancer is susceptible to drugs, these drugs must penetrate the "blood-brain barrier" if they're to treat cancer that's metastasized to the brain. "Mother Nature created this barrier to protect our brains from dangerous substances, but here we need to get through the barrier to deliver the drugs, and that's a problem," says study author Julia Y. Ljubimova, M.D., Ph.D., a research scientist at the Cedars-Sinai Maxine Dunitz Neurosurgical Institute in Los Angeles.
Keith Black, M.D., chairman of Cedars-Sinai's Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute, is the lead research scientist on this project and senior author of the paper. He has studied the blood-brain barrier for about two decades, and his work in this field received the Jacob Javits award from the National Advisory Neurological Disorders and Stroke Council of the National Institutes of Health in June 2000. Since then, research conducted by his team found that the erectile dysfunction drugs sildenafil (Viagra) and vardenafil (Levitra), which inhibit the enzyme phosphodiesterase 5 (PDE5), could increase the permeability of the blood-brain tumor barrier and boost the effectiveness of the chemotherapy drug doxorubicin.
"No matter how effective against cancer a chemotherapeutic agent may be, it can have little impact on brain tumors if it cannot cross the blood-brain tumor barrier," he said. "As we find new drugs that are able to target these tumor cells, it is imperative that we develop better ways to enable the medications to reach their targets."
In the current study, the researchers examined whether PDE5 inhibitors might also increase the blood-brain tumor barrier's permeability to Herceptin, a monoclonal antibody used to treat lung and breast tumors that are positive for HER2/neu. Herceptin is a large molecule that does not easily cross the blood-brain tumor barrier, a limitation that severely reduces its effectiveness at treating brain metastases.
The researchers first measured vardenafil's effects on the permeability of the blood-brain tumor barrier. Using a mouse model, the scientists showed that vardenafil led to a two-fold increase in the amount of Herceptin that reached brain metastases of lung and breast cancers. Next, they examined whether this increase in blood-brain barrier permeability improved Herceptin's effectiveness at treating these brain metastases by giving mice vardenafil in tandem with Herceptin. The results showed that the combination of vardenafil plus Herceptin boosted mean survival by 20 percent, compared to Herceptin alone (72+/-18 days versus 59+/-9 days).
Mice whose tumors were not HER2-positive did not experience the same increase in survival that those with HER2-positive tumors did when given vardenafil, indicating that the survival benefit was indeed due to an increase in the amount of Herceptin reaching the tumors, says Ljubimova.
"Now that we've demonstrated that big molecules can cross the blood-brain tumor barrier, we're going to continue this strategy with other big molecule drugs, such as nanomedicine drugs" says Ljubimova. "This opens a new world for brain tumor treatments."

Citation: Hu J, Ljubimova JY, Inoue S, Konda B, Patil R, et al. (2010) Phosphodiesterase Type 5 Inhibitors Increase Herceptin Transport and Treatment Efficacy in Mouse Metastatic Brain Tumor Models. PLoS ONE 5(4): e10108. doi:10.1371/journal.pone.0010108
Link:
http://www.csmc.edu




PLoS One. 2010 Apr 19;5(4):e10108.
Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models.




Hu J, Ljubimova JY, Inoue S, Konda B, Patil R, Ding H, Espinoza A, Wawrowsky KA, Patil C, Ljubimov AV, Black KL.
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
Abstract

BACKGROUND: Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14)C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14)C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05). CONCLUSIONS/SIGNIFICANCE: These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.

PMID: 20419092 [PubMed - in process]PMCID: PMC2856671Free PMC Article


J Cereb Blood Flow Metab. 2010 Mar 10. [Epub ahead of print]
17-beta-Estradiol: a powerful modulator of blood-brain barrier BCRP activity.

Hartz AM, Mahringer A, Miller DS, Bauer B.
Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota, USA.
The ATP-driven efflux transporter, breast cancer resistance protein (BCRP), handles many therapeutic drugs, including chemotherapeutics, limiting their ability to cross the blood-brain barrier. This study provides new insight into rapid, nongenomic regulation of BCRP transport activity at the blood-brain barrier. Using isolated brain capillaries from rats and mice as an ex vivo blood-brain barrier model, we show that BCRP protein is highly expressed in brain capillary membranes and functionally active in intact capillaries. We show that nanomolar concentrations of 17-beta-estradiol (E2) rapidly reduced BCRP transport activity in the brain capillaries. This E2-mediated effect occurred within minutes and did not involve transcription, translation, or proteasomal degradation, indicating a nongenomic mechanism. Removing E2 after 1 h fully reversed the loss of BCRP activity. Experiments using agonists and antagonists for estrogen receptor (ER)alpha and ERbeta and brain capillaries from ERalpha and ERbeta knockout mice demonstrated that E2 could signal through either receptor to reduce BCRP transport function. We speculate that this nongenomic E2-signaling pathway could potentially be used for targeting BCRP at the blood-brain barrier, in brain tumors, and in brain tumor stem cells to improve chemotherapy of the central nervous system.

Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 March 2010; doi:10.1038/jcbfm.2010.36.

PMID: 20216549 [PubMed - as supplied by publisher]


Curr Opin Mol Ther. 2010 Apr;12(2):168-75.
Telomerase inhibitors for the treatment of brain tumors and the potential of intranasal delivery.

Hashizume R, Gupta N.
University of California San Francisco, Hellen Diller Family Cancer Research Center, Mission Bay, 1450 3rd Street, HD 200, San Francisco, CA 94158-0520, USA. rintaro.hashizume@ucsf.edu
Abstract

A fundamental limitation in the treatment of brain tumors is that < 1% of most therapeutic agents administered systemically are able to cross the blood-brain barrier (BBB). The development of new strategies that circumvent the BBB should increase the likelihood of tumor response to selected therapeutic agents. Intranasal delivery (IND) is a practical, noninvasive method of bypassing the BBB to deliver therapeutic agents to the brain. This technique has demonstrated promising results in the treatment of neurological disorders. Telomerase is a reverse transcriptase that is expressed in the vast majority of malignant gliomas, although not in the healthy brain. Telomerase inhibition can therefore be used as a therapeutic strategy for selectively targeting malignant gliomas. The first successful IND of a telomerase inhibitor as a therapy for brain tumors was GRN-163, an oligonucleotide N3'-->5' thiophosphoramidate telomerase inhibitor, which was successfully administered into intracerebral tumors in rats with no apparent toxicity. GRN-163 exhibited favorable tumor uptake and inhibited tumor growth, leading to prolonged lifespan in treated animals. The IND of telomerase inhibitors represents a new therapeutic approach that appears to selectively kill tumor cells, without inducing toxic effects in the surrounding healthy brain tissue.

PMID: 20373260 [PubMed - indexed for MEDLINE]



PLoS One. 2010 Aug 12;5(8):e12124.
Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells.

Gurung RL, Lim SN, Khaw AK, Soon JF, Shenoy K, Mohamed Ali S, Jayapal M, Sethu S, Baskar R, Hande MP.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.


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Abstract

BACKGROUND: A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells.
METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxic effect of thymoquinone, a component derived from the plant Nigella sativa, was tested on human glioblastoma and normal cells. Our findings demonstrated that glioblastoma cells were more sensitive to thymoquinone-induced antiproliferative effects. Thymoquinone induced DNA damage, cell cycle arrest and apoptosis in the glioblastoma cells. It was also observed that thymoquinone facilitated telomere attrition by inhibiting the activity of telomerase. In addition to these, we investigated the role of DNA-PKcs on thymoquinone mediated changes in telomere length. Telomeres in glioblastoma cells with DNA-PKcs were more sensitive to thymoquinone mediated effects as compared to those cells deficient in DNA-PKcs.
CONCLUSIONS/SIGNIFICANCE: Our results indicate that thymoquinone induces DNA damage, telomere attrition by inhibiting telomerase and cell death in glioblastoma cells. Telomere shortening was found to be dependent on the status of DNA-PKcs. Collectively, these data suggest that thymoquinone could be useful as a potential chemotherapeutic agent in the management for brain tumours.

PMID: 20711342 [PubMed - in process]PMCID: PMC2920825Free PMC Article