CANCER

MODERN DISEASE PREVENTION

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Alas, I am dying beyond my means.
Oscar Wilde (1854 - 1900)

ERIVEDGE™ APPROVED FOR BASAL CELL CARCINOMA
     January, 30 2012 -- The U.S. Food and Drug Administration approved a new medicine for the treatment of adults with basal cell carcinoma, the most common type of skin cancer. ERIVEDGE™ (generically known as vismodegib) treats basal cell carcinoma that has metastasized or patients with locally advanced basal cell cancer who are not candidates for surgery or radiation. ERIVEDGE™ capsules are taken once a day; with or without food.
     ERIVEDGE™ is the first FDA-approved drug for metastatic basal cell carcinoma. This type of cancer is generally slow growing and a painless form of skin cancer that starts in the top layer of the skin. ERIVEDGE™ works by inhibiting the Hedgehog pathway, a molecular pathway that is active in most basal cell cancers and only a few normal tissues, such as hair follicles.
     “Our understanding of molecular pathways involved in cancer, such as the Hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Richard Pazdur, M.D., FDA’s director of the Office of Hematology and Oncology Products at the Center for Drug Evaluation and Research.
     The safety and effectiveness of ERIVEDGE™ was evaluated in a single, multi-center clinical study of 96 patients with locally advanced or metastatic basal cell carcinoma. The clinical study’s primary endpoint was objective response rate (ORR) or the percentage of patients who experienced complete and partial shrinkage or disappearance of the cancerous lesions after treatment. Thirty percent of the patients with metastatic disease receiving ERIVEDGE™ experienced a partial response and 43 percent of patients with locally advanced disease experienced a complete or partial response.
     The most common side effects observed in patients treated with ERIVEDGE™ were muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, distorted sense of taste, decreased appetite, constipation, vomiting, and loss of taste function in the tongue. ERIVEDGE™ is approved by the FDA with a BOXED WARNING alerting patients and health care professionals of the potential risk of death or severe birth effects to a fetus. Pregnancy status must be verified prior to the start of treatment.
     ERIVEDGE™ is marketed by South San Francisco based biotechnology company Genentech, Inc. ERIVEDGE is a registered trademark of Genentech, Inc.
     The first Biopharmaceutical approved for therapeutic use was biosynthetic 'human' insulin made via recombinant DNA technology. Sometimes referred to as rHI (trade name Humulin), it was developed by Genentech and licensed to Eli Lilly to manufacture and market in 1982.

A KEY TARGET FOR ANTI-CANCER THERAPEUTICS
     Geron is a biopharmaceutical company developing first-in-class cancer therapeutics. One of Geron's anti-cancer strategies is to inhibit the activity of telomerase. Telomerase is a rational target for the treatment of cancer, with potentially broad applicability, because most cancers have a high level of telomerase activity and relatively short telomeres compared to normal cells. Inhibiting telomerase may be less toxic to normal cells than conventional chemotherapy or non-specific therapies. The effects of imetelstat on tumor cells have been well characterized in numerous preclinical studies conducted by scientists at Geron and academic collaborators.
     Imetelstat (GRN163L) uses proprietary nucleic acid chemistry. Geron’s unique and proprietary nucleic acid chemistry platform has overcome the inherent hurdles and liabilities that have historically been associated with oligonucleotide-based drugs for human therapeutics. Certain chemical modifications have provided significantly improved binding affinity to the intended target and increased hydrolytic stability, and enabled efficient cellular uptake and biodistribution in vivo.
     This first-in-class compound is a specially designed and modified oligonucleotide, which targets and binds directly to the active site of telomerase with high affinity. The proprietary oligonucleotide chemistry and lipid modification improves binding affinity and stability, and enables good cellular and tissue penetration and biodistribution, even at lower concentrations. The effects of Imetelstat on tumor cells have been well characterized in numerous preclinical studies conducted by scientists at Geron and academic collaborators.
     Imetelstat inhibits telomerase activity and shortens telomeres, leading to the inhibition of cancer cell growth. Imetelstat inhibits the growth of a variety of tumor types in cell culture systems and in rodent models of human cancers (xenograft model), impacting the growth of primary tumors and preventing metastases. Imetelstat has additive and synergistic effects in a variety of tumor cell culture systems and xenograft models when administered in combination with approved anti-cancer agents including, radiation, conventional chemotherapies and targeted therapies. Imetelstat is an effective inhibitor of cancer stem cells (CSCs) from a broad range of tumor types.
     The preclinical data showing the effects of Imetelstat against both the bulk tumor and cancer stem cells, and the activity when combined with approved anti-cancer agents, supports clinical investigation of imetelstat in combination with approved anti-cancer therapies with the potential to improve clinical responses and the duration of response. Based on preclinical data and the results obtained in the Geron sponsored Phase 1 clinical trials, imetelstat is currently being evaluated in four Geron sponsored Phase 2 clinical oncology studies for the following indications: non-small cell lung cancer, metastatic breast cancer, essential thrombocythemia and multiple myeloma. http://www.geron.com/clinical-development

PHOSPHATASE AND TENSIN HOMOLOG LOCATED ON CHROMOSOME 10
Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene. The official name of this gene is “phosphatase and tensin homolog.” PTEN is the gene's official symbol. The PTEN gene is located on the long (q) arm of chromosome 10 at position 23.3. More precisely, the PTEN gene is located from base pair 89,623,194 to base pair 89,728,531 on chromosome 10.
http://ghr.nlm.nih.gov/gene/PTEN

THE IMPORTANCE OF PTEN IN CANCER (Abstract)
The importance of PTEN (phosphatase and tensin homolog located on chromosome 10) in cancer has surpassed all predictions and expectations from the time it was discovered and has qualified this gene as one of the most commonly mutated and deleted tumor suppressors in human cancer. PTEN levels are frequently found downregulated in cancer, even in the absence of genetic loss or mutation. PTEN is heavily regulated by transcription factors, microRNAs, competitive endogenous RNAs (such as the PTEN pseudogene), and methylation, whereas the tumor suppressive activity of the PTEN protein can be altered at multiple levels through aberrant phosphorylation, ubiquitination, and acetylation. These regulatory cues are presumed to play a key role in tumorigenesis through the alteration of the appropriate levels, localization, and activity of PTEN. The identification of all these levels of PTEN regulation raises, in turn, a key corollary question: How low should PTEN level(s) or activity drop in order to confer cancer susceptibility at the organismal level? Our laboratory and others have approached this question through the genetic manipulation of Pten in the mouse. This work has highlighted the exquisite and tissue-specific sensitivity to subtle reductions in Pten levels toward tumor initiation and progression with important implications for cancer prevention and therapy. Cancer Res; 71(3); 629–33. ©2011 AACR.
Arkaitz Carracedo, Andrea Alimonti, and Pier Paolo Pandolfi. PTEN Level in Tumor Suppression: How Much Is Too Little? ABSTRACT. Cancer Res February 1, 2011 71:629-633; Published OnlineFirst January 25, 2011; doi:10.1158/0008-5472.CAN-10-2488. [OnlineFirst articles are published online before they appear in a regular issue of the journal, Cancer Research.] Cancer Research [Print ISSN: 0008-5472; Online ISSN: 1538-7445] is published twice a month, one volume/year, by the American Association for Cancer Research, Inc.

CHROMOSOME ABNORMALITIES
     A chromosome abnormality reflects an abnormality of chromosome number or structure. There are many types of chromosome abnormalities. However, they can be organized into two basic groups:
Numerical Abnormalities—When an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy). An example of a condition caused by numerical abnormalities is Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). Turner Syndrome is an example of monosomy, where the individual (in this case a female) is born with only one sex chromosome, an X.
Structural Abnormalities—When the chromosome's structure is altered. Structural Abnormalities can take several forms:
Deletions— A portion of the chromosome is missing or deleted.
Duplications— A portion of the chromosome is duplicated, resulting in extra genetic material.
Translocations— When a portion of one chromosome is transferred to another chromosome. There are two main types of translocations. In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere.
Inversions— A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted. And,
Rings— A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.
     Most chromosome abnormalities occur as an accident in the egg or sperm. Therefore, the abnormality is present in every cell of the body. Some abnormalities, however, can happen after conception, resulting in mosaicism, where some cells have the abnormality and some do not. Chromosome abnormalities can be inherited from a parent (such as a translocation) or be "de novo" (new to the individual). This is why chromosome studies are often performed on parents when a child is found to have an abnormality.
     Chromosome abnormalities usually occur when there is an error in cell division. There are two kinds of cell division. Mitosis results in two cells that are duplicates of the original cell. In other words, one cell with 46 chromosomes becomes two cells with 46 chromosomes each. This kind of cell division occurs throughout the body, except in the reproductive organs. This is how most of the cells that make up our body are made and replaced. Meiosis results in cells with half the number of chromosomes, 23 instead of the normal 46. These are the eggs and sperm.
     In both processes, the correct number of chromosomes is supposed to end up in the resulting cells. However, errors in cell division can result in cells with too few or too many copies of a chromosome. Errors can also occur when the chromosomes are being duplicated.
     Other factors that can increase the risk of chromosome abnormalities include Maternal Age and Environment.
Maternal Age— Women are born with all the eggs they will ever have. Therefore, when a woman is 30 years old, so are her eggs. Some researchers believe that errors can crop up in the eggs' genetic material as they age over time. Therefore, older women are more at risk of giving birth to babies with chromosome abnormalities than younger women. Since men produce new sperm throughout their life, paternal age does not increase risk of chromosome abnormalities.
Environment— Although there is no conclusive evidence that specific environmental factors cause chromosome abnormalities, it is still a possibility that the environment may play a role in the occurence of genetic errors.
     The National Human Genome Research Institute (NHGRI) has produced a series of fact sheets to provide an overview of the institute, explore the social implications of genetic research, and explain complex genetic concepts and research techniques to a non-scientific audience. Teachers, students and the general public alike will find the materials clearly written and easy to understand. http://www.genome.gov/10000202
Fact Sheet, How do chromosome abnormalities happen? Chromosome Abnormalities, Fact Sheets About Science. Courtesy: National Institutes of Health, National Human Genome Research Institute. Last Updated October 13, 2011.

BRAIN METASTASES CLINICAL TRIALS
     The incidence of metastatic disease in the brain is increasing. This may be due to a number of factors, such as improved central nervous system (CNS) screening and imaging, but also improved therapies to treat disease outside of the brain, which result in prolonged survival and therefore increase the cumulative risk of a tumor metastasizing to the brain. Lung cancer is the most common cause of brain metastases, followed by breast cancer.
     Brain metastases are associated with considerable morbidity and mortality, and there are currently no approved drug therapies for brain metastases. Diseases of the brain, such as brain cancers, are very difficult to treat because most drugs, including oncology drugs, cannot reach the brain at levels that are clinically therapeutic. Drugs are unable to reach the brain because of the blood-brain barrier. Transport across the blood-brain barrier and into tumors is critical for developing effective treatments for cancer in the brain.
     The blood-brain barrier has two major functions: to protect the brain and regulate brain homeostasis. The brain is protected by tight junctions between the endothelial cells of the capillaries in the brain and the presence of active efflux pumps (transport proteins that are involved in the extrusion of toxic substances). As a consequence, the overwhelming majority of small molecules, proteins and peptides do not cross the blood-brain barrier. However, the brain needs many molecules for survival, including insulin, transferrin and low-density lipoprotein.
     Receptors present on the blood-brain barrier actively transport these molecules from the blood into the brain. For example, insulin binds to the insulin-receptor which allows it to enter the brain. This mechanism is known as receptor-mediated transcytosis.
     The lipoprotein receptor-related protein-1 (LRP-1) receptor is one of the most highly expressed receptors at the blood-brain barrier and naturally transports numerous proteins to the brain. By linking the LRP-1 peptide binding sequence to therapeutic agents, the receptor can be targeted to exploit this native mechanism for crossing the blood-brain barrier to deliver therapeutic agents into the brain.
     Geron Corporation is built on a foundation of scientific innovation. Geron's GRN1005 is a peptide-drug conjugate (PDC) that consists of three molecules of paclitaxel covalently linked to a proprietary 19 amino acid peptide (AngioPep-2) to target LRP-1. Paclitaxel (also called Taxol) is an approved and effective anti-cancer drug that in its naked form cannot penetrate the brain.
     GRN1005 is designed to cross the blood-brain barrier via LRP-1 receptor mediated transcytosis. Since LRP-1 is also up-regulated in many tumors, entry into tumor cells may occur via LRP-1 mediated endocytosis once across the blood-brain barrier and in the brain. LRP-1 is up-regulated in cancers in the brain as well other organs, enabling entry into tumors in the brain and in the periphery using the same receptor-mediated pathway.
     Geron is conducting a clinical trial to evaluate the effect of GRN1005 in patients whose breast cancer has metastasized to the brain. In this Phase 2 clinical trial, Geron's clinical investigators and researchers are evaluating how GRN1005 may affect the intra-cranial response rates of patients when used alone or in combination with trastuzumab (also Called Herceptin), a monoclonal antibody used in the treatment of metastatic breast cancer.
     Geron Corporation is also conducting a clinical trial to study the effect of GRN1005 in patients whose non-small cell lung cancer (NSCLC) has metastasized to the brain. In this Phase 2 clinical trial, Geron's clinical researchers and investigators are evaluating how GRN1005 may impact overall objective response rates in both intra-cranial and extra-cranial disease. http://www.geron.com/clinical-development