Ligumsky H.,Aviv Sourasky Medical Center |
Ligumsky H.,Tel Aviv University |
Rubinek T.,Aviv Sourasky Medical Center |
Merenbakh-Lamin K.,Aviv Sourasky Medical Center |
And 8 more authors.
Molecular Cancer Research | Year: 2015
Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the b-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Over-expression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities. Implications: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer. © 2015 American Association for Cancer Research.
News Article | December 5, 2016
Following a successful diet, many people are dismayed to find their weight rebounding - an all-too-common phenomenon termed "recurrent" or "yo-yo" obesity. Worse still, the vast majority of recurrently obese individuals not only rebound to their pre-dieting weight but also gain more weight with each dieting cycle. During each round of dieting-and-weight-regain, their proportion of body fat increases, and so does the risk of developing the manifestations of metabolic syndrome, including adult-onset diabetes, fatty liver and other obesity-related diseases. As reported today in Nature, researchers at the Weizmann Institute of Science have shown in mice that intestinal microbes - collectively termed the gut microbiome - play an unexpectedly important role in exacerbated post-dieting weight gain, and that this common phenomenon may in the future be prevented or treated by altering the composition or function of the microbiome. The study was performed by research teams headed by Dr. Eran Elinav of the Immunology Department and Prof. Eran Segal of the Computer Science and Applied Mathematics Department. The researchers found that after a cycle of gaining and losing weight, all the mice's body systems fully reverted to normal - except the microbiome. For about six months after losing weight, post-obese mice retained an abnormal "obese" microbiome. "We've shown in obese mice that following successful dieting and weight loss, the microbiome retains a 'memory' of previous obesity," says Elinav. "This persistent microbiome accelerated the regaining of weight when the mice were put back on a high-calorie diet or ate regular food in excessive amounts." Segal elaborates: "By conducting a detailed functional analysis of the microbiome, we've developed potential therapeutic approaches to alleviating its impact on weight regain." The study was led by Christoph Thaiss, a Ph.D. student in Elinav's lab. Thaiss collaborated with master's student Shlomik Itav of the Elinav lab, Daphna Rothschild, a Ph.D. student of Segal's lab, as well as with other scientists from Weizmann and elsewhere. In a series of experiments, the scientists demonstrated that the makeup of the "obese" microbiome was a major driver of accelerated post-dieting weight gain. For example, when the researchers depleted the intestinal microbes in mice by giving them broad-spectrum antibiotics, the exaggerated post-diet weight gain was eliminated. In another experiment, when intestinal microbes from mice with a history of obesity were introduced into germ-free mice (which, by definition, carry no microbiome of their own), their weight gain was accelerated upon feeding with a high-calorie diet, compared to germ-free mice that had received an implant of intestinal microbes from mice with no history of weight gain. Next, the scientists developed a machine-learning algorithm, based on hundreds of individualized microbiome parameters, which successfully and accurately predicted the rate of weight regain in each mouse, based on the characteristics of its microbiome after weight gain and successful dieting. Furthermore, by combining genomic and metabolic approaches, they then identified two molecules driving the impact of the microbiome on regaining weight. These molecules - belonging to the class of organic chemicals called flavonoids that are obtained through eating certain vegetables - are rapidly degraded by the "post-dieting" microbiome, so that the levels of these molecules in post-dieting mice are significantly lower than those in mice with no history of obesity. The researchers found that under normal circumstances, these two flavonoids promote energy expenditure during fat metabolism. Low levels of these flavonoids in weight cycling prevented this fat-derived energy release, causing the post-dieting mice to accumulate extra fat when they were returned to a high-calorie diet. Finally, the researchers used these insights to develop new proof-of-concept treatments for recurrent obesity. First, they implanted formerly obese mice with gut microbes from mice that had never been obese. This fecal microbiome transplantation erased the "memory" of obesity in these mice when they were re-exposed to a high-calorie diet, preventing excessive recurrent obesity. Next, the scientists used an approach that is likely to be more unobjectionable to humans: They supplemented post-dieting mice with flavonoids added to their drinking water. This brought their flavonoid levels, and thus their energy expenditure, back to normal levels. As a result, even on return to a high-calorie diet, the mice did not experience accelerated weight gain. Segal said: "We call this approach 'post-biotic' intervention. In contrast to probiotics, which introduce helpful microbes into the intestines, we are not introducing the microbes themselves but substances affected by the microbiome, which might prove to be more safe and effective." Recurrent obesity is an epidemic of massive proportions, in every meaning of the word. "Obesity affects nearly half of the world's adult population, and predisposes people to common life-risking complications such as adult-onset diabetes and heart disease," says Elinav. "If the results of our mouse studies are found to be applicable to humans, they may help diagnose and treat recurrent obesity, and this, in turn, may help alleviate the obesity epidemic." Also taking part in the study were Mariska Meijer, Maayan Levy, Claudia Moresi, Lenka Dohnalova, Sofia Braverman, Shachar Rozin, Dr. Mally Dori-Bachash and Staff Scientist Hagit Shapiro of the Immunology Department, Staff Scientists Drs. Yael Kuperman and Inbal Biton, and Prof. Alon Harmelin of the Veterinary Resources Department, and Dr. Sergey Malitsky and Prof. Asaph Aharoni of the Plant and Environmental Sciences Department - all of the Weizmann Institute of Science, as well as Prof. Arieh Gertler of the Hebrew University of Jerusalem and Prof. Zamir Halpern of the Tel-Aviv Sourasky Medical Center. Dr. Eran Elinav's research is supported by the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; the Else Kroener Fresenius Foundation; John L. and Vera Schwartz, Pacific Palisades, CA; the Rising Tide Foundation; Andrew and Cynthia Adelson, Canada; Yael and Rami Ungar, Israel; Donald L. Schwarz, Sherman Oaks, CA; Leesa Steinberg, Canada; Aaron Edelheit, Boca Raton, FL; Jack N. Halpern, New York, NY; and the Lawrence and Sandra Post Family. Dr. Elinav is the Incumbent of the Rina Gudinski Career Development Chair. Prof. Eran Segal's research is supported by the Crown Human Genome Center, which he heads; the Else Kroener Fresenius Foundation; Donald L. Schwarz, Sherman Oaks, CA; Jack N. Halpern, New York, NY; and Leesa Steinberg, Canada. The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
News Article | December 13, 2016
Patient Enrollment in the United States and Canada Ongoing SAN DIEGO, Dec. 13, 2016 /PRNewswire/ -- Tocagen Inc., a clinical-stage, cancer-selective gene therapy company, today announced its randomized, controlled Phase 2/3 clinical trial, called Toca 5, is now enrolling patients in Israel. Enrollment in the trial is ongoing in the United States and Canada. The study compares a cancer-selective virus, Toca 511 (vocimagene amiretrorepvec), in combination with Toca FC (extended-release 5-fluorocytosine) to standard of care in patients with first or second recurrence of glioblastoma or anaplastic astrocytoma who are undergoing resection. "Brain cancer remains one of the most aggressive and difficult-to-treat cancers, and there is significant need for new approaches. We are excited to be able to offer the Toca 5 gene therapy trial to patients in Israel," said Rachel Grossman, M.D., attending neurosurgeon at Tel-Aviv Sourasky Medical Center and principal investigator for the Toca 5 clinical trial in Israel. "This investigational treatment is designed to activate the patient's immune system selectively against the cancer, while maintaining a favorable safety profile." "Receiving a brain cancer diagnosis is devastating for patients and their families, and if the tumor returns there are very few treatment options," said Alexander Lossos, M.D., head of the neuro-oncology center at the Hadassah Medical Center, which enrolled the first patient in Israel. "Our dedicated brain tumor care team is delighted to be the first clinical site in Israel to randomize a patient for this new study." The primary endpoint for the Toca 5 clinical trial is overall survival with secondary endpoints including objective response rate. Investigators may choose chemotherapy (lomustine or temozolomide) or antiangiogenic therapy (bevacizumab) for the control arm. More information about the clinical trial can be found at www.tocagen.com/toca5. Added Zvi Ram, M.D., Ph.D., department director of neurosurgery at Tel-Aviv Sourasky Medical Center, "The Phase 1 results for this treatment in patients with recurrent high grade glioma showed encouraging data including a favorable safety profile, durable tumor responses and promising survival. We now eagerly anticipate the results from the randomized Toca 5 study." High grade gliomas are among the most common and aggressive primary brain cancers. The two most common forms of high grade glioma are glioblastoma and anaplastic astrocytoma. Standard treatment for newly diagnosed high grade glioma includes safe surgical removal of as much of the tumor as possible followed by radiation therapy and chemotherapy. Despite these treatments, the tumor often recurs. Median survival after recurrence is approximately seven to nine months. A total of 126 patients have been treated in Tocagen's Phase 1 ascending-dose studies. Clinical data were recently published in Science Translational Medicine. In the subset of patients in the higher dose cohorts that mirror the patient population under evaluation in the ongoing Toca 5 trial, a clinical benefit rate of 41.7% was reported at the 21st Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology. This included 3 complete responses, 2 partial responses and 5 patients with stable disease (N=24). All patients with an objective response remain alive and the median duration of response is at least 26.7 months. A summary of clinical data from Tocagen's ongoing Phase 1 clinical trials can be found on Tocagen's website. Tocagen's lead product candidate is a combination of an investigational biologic, Toca 511, and an investigational oral tablet, Toca FC. Toca 511 encodes a prodrug activator enzyme, CD. Its selective delivery to cancer cells means that the infected cancer cells carry the CD gene and produce CD protein. Toca FC is an orally administered, proprietary extended-release formulation of 5-fluorocytosine (5-FC), a prodrug that is inactive as an anti-cancer drug. Within Toca-511-infected cancer cells that are producing CD, Toca 511 is designed to convert Toca FC into the anti-cancer drug, 5-fluorouracil (5-FU) at local high concentrations. In addition to the direct killing of Toca 511-infected cancer cells, 5-FU kills neighboring uninfected cancer cells and immunosuppressive myeloid cells including myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAM) in the tumor. Tocagen is a clinical-stage, cancer-selective gene therapy company developing first-in-class, broadly applicable product candidates designed to activate a patient's immune system against their own cancer. The company is developing its lead investigational product candidate, Toca 511 (vocimagene amiretrorepvec) & Toca FC (extended-release 5-fluorocytosine), initially for the treatment of recurrent high grade glioma (HGG), a disease with significant unmet medical need. Tocagen has initiated the Phase 2 portion of a randomized, controlled Phase 2/3 clinical trial of Toca 511 & Toca FC in patients with recurrent HGG, which is designed to serve as a potential registrational trial. More information about the clinical trial can be found at www.tocagen.com/toca5. Tocagen has initiated a clinical trial of Toca 511 & Toca FC in metastatic cancers, including colorectal, pancreatic, lung, breast, renal and melanoma. Tocagen obtained Fast Track designation from the U.S. Food and Drug Administration for Toca 511 & Toca FC as a treatment of recurrent HGG and Orphan drug designation for the treatment of glioblastoma multiforme (GBM), a subset of HGG. Tocagen has received grant support from leading brain cancer foundations, including Accelerate Brain Cancer Cure (ABC2), National Brain Tumor Society (NBTS), American Brain Tumor Association (ABTA), Musella Foundation and Voices Against Brain Cancer (VABC). For more information, visit www.tocagen.com or follow @Tocagen.