Carrier cell-based delivery of replication-competent HSV-1 mutants enhances antitumor effect for ovarian cancer
Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. We have developed replication-competent attenuated herpes simplex virus type 1 (HSV-1) mutants, named HF10 and Hh101, which have been evaluated for their oncolytic activities. However, the host immune system remains a significant obstacle to effective intraperitoneal administration of these viruses in the clinical setting.
In this study, we investigated the use of these HSV-1 mutants as oncolytic agents against ovarian cancer and the use of human peritoneal mesothelial cells (MCs) as carrier cells for intraperitoneal therapy. MCs were efficiently infected with HSV-1 mutants, and MCs loaded with HSV-1 mutants caused cell killing adequately when cocultured with cancer cells in the presence or absence of HSV antibodies. In a mouse xenograft model of ovarian cancer, the injection of infected carrier cells led to a significant reduction of tumor volume and prolonged survival in comparison with the injection of virus alone.
Our results indicate that replication-competent attenuated HSV-1 exerts a potent oncolytic effect on ovarian cancer, which may be further enhanced by the utilization of a carrier cell delivery system, based on amplification of viral load and possibly on avoidance of neutralizing antibodies.
S Fujiwara1,2, A Nawa1, C Luo2, M Kamakura2, F Goshima2, C Kondo3, T Kiyono4, F Kikkawa1 and Y Nishiyama2
Cancer Gene Therapy (2011) 18, 77–86; doi:10.1038/cgt.2010.53; published online 1 October 2010
Read Complete Article
**********************************************************************
For Women with BRCA Mutations, Prophylactic Surgery Reduces Cancer Risk
Adapted from the NCI Cancer Bulletin, vol. 7/no. 17, September 7, 2010
Prophylactic surgery to remove the breasts and ovaries is an effective way to reduce the risk of breast and ovarian cancer among women with inherited mutations in the BRCA1 or BRCA2 genes, according to one of the largest prospective studies on the subject to date. The findings, published September 1, 2010, in JAMA, provide estimates of the benefits of mastectomy and salpingo-oophorectomy (removal of the ovaries and fallopian tubes) in reducing the risk of cancer and death among carriers of disease-associated BRCA1 or BRCA2 gene mutations.
These mutations confer a 56 to 84 percent lifetime risk of breast cancer.
The results also show that the risk reduction occurs regardless of whether the mutation is located in theBRCA1 or BRCA2 gene or whether a woman had cancer previously. Researchers at 22 medical centers in Europe and North America tracked nearly 2,500 women with a disease-associated BRCA1 or BRCA2mutation. Almost half of the women had one of the prophylactic surgeries.
During 3 years of follow-up, none of the women who had a mastectomy developed breast cancer, while 7 percent of the women who didn’t have the surgery were diagnosed with breast cancer. And only 1 percent of the women who underwent risk-reducing salpingo-oophorectomy developed ovarian cancer during 6 years of follow-up, compared with 6 percent of women who did not have the surgery.
“This study reinforces the message that genetic testing has value,” said Timothy Rebbeck, Ph.D., of the University of Pennsylvania, the study’s senior author. Women who know that they have inherited a high-risk mutation can, with the appropriate genetic counseling, take steps to reduce their risk of cancer through prophylactic surgery, he continued.
Although many women choose prophylactic surgery, many do not, the study authors noted. Just 10 percent of the women in the study chose prophylactic mastectomy and 38 percent chose salpingo-oophorectomy. “For women who have these genetic mutations, we think we can save lives,” Dr. Rebbeck stressed. “And that’s an important message.”
The authors of an accompanying editorial in JAMA echoed this message and noted that options for prophylactic surgeries have changed and improved. For example, laparoscopic salpingo-oophorectomy is a relatively low-risk procedure that can be done in an outpatient setting, while new techniques for mastectomy produce a more natural appearance, wrote Laura Esserman, M.D., of the University of California, San Francisco, and Virginia Kaklamani, M.D., of Northwestern University.
http://www.cancer.gov/clinicaltrials/results/prophylactic-surgery0910
*********************************************************************************
Miracle Cancer Pill
Dr Gail Roboz said that Gleevac is a life changing drug with a new paradigm for cracking the case of cancer. Dr Oz said the bigger question becomes can we unlock the mysteries of other cancers now too? Dr Oz showed a diagram of a femur bone, which is one of the biggest bones in your body. Inside of the bone are red blood cells that carry oxygen and white blood cells that defend your body. Inside of the white blood cells are chromosomes with your DNA in them. If the DNA from two chromosomes cross and get mixed, then you can start to have problems where your body starts to produce more white blood cells. Soon your bone marrow gets too much white blood cells – and too much of a good thing is never good – the cells turn into sociopaths.
Current cancer treatments like chemotherapy work by destroying and eradicating not only the cancer, but your own healthy normal cells as well. If you could just turn off the protein that is causing white blood cells to grow out of control, then you can kill the cancer without killing your normal cells, which makes this a new paradigm for curing cancer.
Dr. Brian Druker said that the next step is to expand to other cancers and to see how we can prevent cancer altogether. For example, there is a gene that predisposes women to an 80% risk of cancer. Rather than removing a woman’s breasts and ovaries, it would be great if you could take a medication as a preventative measure to prevent cancer.
Tracey, a young girl, had Leukemia and was treated by Gleevec, which she said is one of the reasons she is probably alive today. Tracey said that if everyone wants to help, they should sign up on a bone marrow registry. So please, if you can, please get registered at your local bone marrow registry to help those with Leukemia.
**********************************************************************************
Prostaglandin E Receptor EP1 Suppresses Breast Cancer Metastasis and Is Linked to Survival Differences and Cancer Disparities
Cyclooxygenase-2 is frequently overexpressed and associated with poor prognosis in breast cancer. The cyclooxygenase-2 product prostaglandin E2 elicits cellular responses through four G-protein–coupled receptors, designated EP1 to EP4, coupled to distinct intracellular signaling pathways. EP4, expressed on malignant breast cells, promotes metastasis; however, a role for EP1 in metastasis has not been investigated. Using a murine model of metastatic breast cancer, we now show that pharmacologic antagonism of EP1 with SC19220 or AH6809 promoted lung colonization of mammary tumor cells by 3.7- to 5.4-fold. Likewise, reducing EP1 gene expression by shRNA also increased metastatic capacity relative to cells transfected with nonsilencing vector but did not affect the size of transplanted tumors. Examination of invasive ductal carcinomas by immunohistochemistry shows that EP1 was detected in both the cytoplasm and nucleus of benign ducts as well as malignant cells in some samples, but was absent or limited to either the nucleus or cytoplasm in other malignant samples. Overall survival for women with tumors that were negative for nuclear EP1 was significantly worse than for women with EP1 expression (P = 0.008). There was no difference in survival for women with differences in cytoplasmic EP1 expression (P = 0.46). Comparing EP1 mRNA in breast tumors from African American and European American women revealed that many more African American breast tumors lacked detectable EP1 mRNA (P = 0.04). These studies support the hypothesis that EP1 functions as a metastasis suppressor and that loss of nuclear EP1 is associated with poorer overall survival and may contribute to disparities in outcome in different populations. Mol Cancer Res; 8(10); 1310–8. ©2010 AACR.
Mol Cancer Res October 2010 8;1310.
Molecular Cancer Research
************************************************************************************Critical Roles of DMP1 in HumanEpidermal Growth FactorReceptor 2/neu-Arf-p53
Signaling and Breast Cancer Development
Human epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated cells while it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3′-kinase-Akt-NF-κB pathway, which in turn stimulatedArf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpression. Both Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neumice, and mammary tumorigenesis was significantly accelerated in both Dmp1+/− andDmp1−/− mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50% of wild-type HER2/neu carcinomas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1+/−, Dmp1−/−, and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis.
Molecular Cancer Research
************************************************************************************Critical Roles of DMP1 in HumanEpidermal Growth FactorReceptor 2/neu-Arf-p53
Signaling and Breast Cancer Development
Human epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated cells while it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3′-kinase-Akt-NF-κB pathway, which in turn stimulatedArf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpression. Both Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neumice, and mammary tumorigenesis was significantly accelerated in both Dmp1+/− andDmp1−/− mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50% of wild-type HER2/neu carcinomas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1+/−, Dmp1−/−, and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis.
Cancer Res; 70(22); 9084–94. ©2010 AACR.
******************************************************************************************************
Uterine Cancer Update:
Uterine Cancer Update:
LONDON (Reuters) – A nеw category οf initial cancer drug сουld bе the intensity pick tο customary chemotherapy fοr women wіth modernized endometrial οr uterine cancer, scientists ѕаіd οn Wednesday.
Researchers frοm London’s Institute οf Cancer Research (ICR) found thаt drug well known аѕ PARP inhibitors wеrе аblе tο kіll οff endometrial cancer cells іn lab meals аnd ѕаіd thеіr commentary ѕhουld right away swell іntο tests οn tellurian patients.
Several vast drugmakers, together with Abbott, Merck, Pfizer, Sanofi-Aventis аnd AstraZeneca, аrе building PARP inhibitors, whісh work bу restraint DNA correct mechanisms іn cancer cells, stalling thе dungeon cycle аnd heading tο dungeon death.
“Thеrе аrе the couple of curative companies thаt аrе іn discussions wіth υѕ аt thе impulse wіth thе thουght οf contrast PARP inhibitors іn thіѕ context,” ѕаіd Jorge Reis-Filho, whο led thе investigate οn uterine cancer.
AstraZeneca’s initial PARP drug Olaparib аnd Sanofi’s BSI-201 аrе thе farthest forward іn development, аnd formula οf Sanofi’s drug іn breast cancer ѕhοwеd thіѕ week thаt іt hеlреd women wіth аn assertive form οf thе mildew live аn normal οf scarcely 5 months longer.
PARP іѕ tiny fοr “poly (ADP-ribose) polymerase,” whісh іѕ used bу cancer cells tο correct DNA hυrt. Bу restraint thе enzyme, thе drug іѕ written tο criticise thе capability οf cancer cells tο reanimate themselves.
Reis-Filho’s team, whose investigate wаѕ published іn thе biography Science Translational Medicine, found thаt thе erasure οf the gene called PTEN іѕ pass tο hοw PARP inhibitors work аnd ѕаіd thаt around 80 percent οf cases οf the usual sort οf cancer οf thе uterus hаνе thіѕ gene mutation.
“Thеrе іѕ the transparent attribute in between PTEN detriment аnd attraction tο PARP inhibitors,” ѕаіd Konstantin Dedes οf thе ICR, whο аlѕο worked οn thе study.
“PTEN іѕ lіkе the predictive pen fοr tumors thаt good frοm PARP predicament аnd since thаt around 80 percent οf thеѕе cancers hаνе PTEN gene turn … іt wουld bе really fаscіnаtіng tο exam thіѕ anticipating іn clinical trials.”
According tο thе U.S. National Cancer Institute (NCI), uterine cancer, whісh customarily occurs аftеr menopause, іѕ thе mοѕt usual sort οf gynecologic cancer іn thе United States. Thіѕ year, іt іѕ estimated thаt some-more thаn 43,000 women wіll bе diagnosed wіth іt, аnd scarcely 8,000 wіll die οf іt.
******************************************************************************************************************************
New Cancer Vaccine with Promise
New Cancer Vaccine with Promise
Induction of the glucocorticoid-induced leucine zipper gene limits the efficacy of dendritic cell vaccines
Cancer Gene Therapy 18, 563-570 (August 2011) | doi:10.1038/cgt.2011.23
, , and
Abstract
Dendritic cell (DC) vaccines have shown great promise in generating antitumor immune responses but have generally fallen short of producing durable cures. Determining mechanisms by which these vaccines fail will provide one strategy toward improving their success. Several manipulations of DCs have improved their migration and longevity, but the immune inhibitory environment surrounding tumors provides a powerful suppressive influence. To determine the mechanisms by which DCs at the site of the tumor convert to a suppressive phenotype, we evaluated pathways in DCs that become expressed at the tumor site. Our results revealed that tumors lead to induction of the glucocorticoid-induced leucine zipper (GILZ) gene in DCs, and that this gene is critical for the development of tumor-induced tolerance of both DCs and T cells. Previous data suggested that GILZ is a pivotal gene in the balance between activation and tolerance of DCs. Our new data show that GILZ is highly upregulated in DCs in the tumor microenvironment in vivo and that blockade of this gene in DC vaccines significantly improves long-term survival. These results suggest that GILZ may be an ideal candidate gene to target for novel immune-based tumor therapies.
