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Posts Tagged ‘TP53’


Live 12:00 – 1:00 P.M  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health : October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

12.00 The Italian Mediterranean Diet as a Model of Identity of a People with a Universal Good to Safeguard Health?

Prof. Antonino De Lorenzo, MD, PhD.

Director of the School of Specialization in Clinical Nutrition, University of Rome “Tor Vergata”

It is important to determine how our bodies interacts with the environment, such as absorption of nutrients.

Studies shown here show decrease in life expectancy of a high sugar diet, but the quality of the diet, not just the type of diet is important, especially the role of natural probiotics and phenolic compounds found in the Mediterranean diet.

The WHO report in 2005 discusses the unsustainability of nutrition deficiencies and suggest a proactive personalized and preventative/predictive approach of diet and health.

Most of the noncommunicable diseases like CV (46%) cancer 21% and 11% respiratory and 4% diabetes could be prevented and or cured with proper dietary approaches

Italy vs. the US diseases: in Italy most disease due to environmental contamination while US diet plays a major role

The issue we are facing in less than 10% of the Italian population (fruit, fibers, oils) are not getting the proper foods, diet and contributing to as we suggest 46% of the disease

The Food Paradox: 1.5 billion are obese; we notice we are eating less products of quality and most quality produce is going to waste;

  •  growing BMI and junk food: our studies are correlating the junk food (pre-prepared) and global BMI
  • modern diet and impact of human health (junk food high in additives, salt) has impact on microflora
  • Western Diet and Addiction: We show a link (using brain scans) showing correlation of junk food, sugar cravings, and other addictive behaviors by affecting the dopamine signaling in the substantia nigra
  • developed a junk food calculator and a Mediterranean diet calculator
  • the intersection of culture, food is embedded in the Mediterranean diet; this is supported by dietary studies of two distinct rural Italian populations (one of these in the US) show decrease in diet
  • Impact of diet: have model in Germany how this diet can increase health and life expectancy
  • from 1950 to present day 2.7 unit increase in the diet index can increase life expectancy by 26%
  • so there is an inverse relationship with our index and breast cancer

Environment and metal contamination and glyphosate: contribution to disease and impact of maintaining the healthy diet

  • huge problem with use of pesticides and increase in celiac disease

12:30 Environment and Health

Dr. Iris Maria Forte, PhD.

National Cancer Institute “Pascale” Foundation | IRCCS · Department of Research, Naples, Italy

Cancer as a disease of the environment.  Weinberg’s hallmarks of Cancer reveal how environment and epigenetics can impact any of these hallmarks.

Epigenetic effects

  • gene gatekeepers (Rb and P53)
  • DNA repair and damage stabilization

Heavy Metals and Dioxins:( alterations of the immune system as well as epigenetic regulations)

Asbestos and Mesothelioma:  they have demonstrated that p53 can be involved in development of mesothelioma as reactivating p53 may be a suitable strategy for therapy

Diet, Tomato and Cancer

  • looked at tomato extract on p53 function in gastric cancer: tomato extract had a growth reduction effect and altered cell cycle regulation and results in apoptosis
  • RBL2 levels are increased in extract amount dependent manner so data shows effect of certain tomato extracts of the southern italian tomato (     )

Antonio Giordano: we tested whole extracts of almost 30 different varieties of tomato.  The tomato variety  with highest activity was near Ravela however black tomatoes have shown high antitumor activity.  We have done a followup studies showing that these varieties, if grow elsewhere lose their antitumor activity after two or three generations of breeding, even though there genetics are similar.  We are also studying the effects of different styles of cooking of these tomatoes and if it reduces antitumor effect

please see post https://news.temple.edu/news/2017-08-28/muse-cancer-fighting-tomatoes-study-italian-food

 

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BIO 2018! June 4-7, 2018 at Boston Convention & Exhibition Center

LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

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Li -Fraumeni Syndrome and Pancreatic Cancer

Curator: Marzan Khan, B.Sc.

Li-Fraumeni syndrome (LFS) is a condition that makes individuals prone to developing a wide variety of cancers that occur early on in life, the most common types being- soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemia. (1) Pancreatic cancer is minimally associated with the condition. (2) A survey found the presence of pancreatic cancer in only 1% of 475 tumor samples collected from 91 families who were carriers of p53 mutations, with half of them having LFS. The incidence of breast cancer amongst them was the highest -24%. (2) Pancreatic carcinoma in LFS patients usually occurs in the later stages of life. (3)

The underlying cause of LFS is germline mutations in TP53 gene on chromosome 17p, that encodes the transcription factor p53, crucial in cell cycle regulation and the repair of damaged and/or abnormal cells. (4) In the majority of cases, this mutation is obtained by inheritance. (5) De-novo germline mutations in p53 occur in 7%-20% of the cases. (5)

A person showing symptoms of any type of cancer at an early age or having first or second-degree relatives with cancer are at risk of developing LFS. (5) That is why tracing family history is an important part of diagnosis in LFS patients. Genetic testing can confirm mutations present in the gene, however, there are controversial ethical issues regarding their use, particularly in children and fetuses.

In patients with LFS, it is important to control the manifestations of the disease. They should be monitored closely so that any new cancers that arise are diagnosed and treated during the early stages. (6) Patients are also at risk of developing radiation-induced second and third primary tumors. (6) Therefore, radiation and alkylating agents should be used minimally (6) People at risk can be cautioned to avoid exposure to carcinogens such as sunlight, cigarette smoke, and alcohol consumption. (5) Therapeutic approaches that are aimed at restoring wild-type p53 by gene therapy as well as reactivating non-functional p53 by the use of small-molecule drugs are currently being investigated in many cancers. (7) Unlike radiation therapy, these small-molecule drugs are non-toxic to healthy cells, thus eliminating the risk of forming new tumors.

So far, PRIMA-1 has proven to be quite effective at correcting non-functional p53. (8) PRIMA-1 is changed to its methylated form, PRIMA-1MET   that forms covalent adducts to thiol groups in the mutated protein and modifies them. (8) As a result, p53 regains its ability to destroy malignant cells. (8) A research study also found that PRIMA-1 induces apoptosis and increases the sensitivity of pancreatic cancer cells to various chemotherapeutic agents. (9)

  1. Magali Olivier, David E. Goldgar, Nayanta Sodha, Hiroko Ohgaki, Paul Kleihues, Pierre Hainaut and Rosalind A. Eeles. Li-Fraumeni and Related Syndromes. Cancer Res October 15 2003 63 (20) 6643-6650 http://cancerres.aacrjournals.org/content/63/20/6643.abstract
  2. Kleihues P, Schauble B, zur Hausen H, et al. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 1997; 150:1-13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858532/
  3. John P. Neoptolemos, Raul Urrutia, James L. Abbruzzese, Markus W. Buchler. Pancreatic Cancer. 2010.1st ed, pp-6, 2010, Springer, Verlag, New York
  4. Mishra B and Patel RR. Gene Therapy for Treatment of Pancreatic Cancer. Austin Therapeutics. 2014;1(1): 10. https://books.google.ca/books?id=NmBB5ZoKkk4C&pg=PA6&lpg=PA6&dq=connection+between+li+fraumeni+and+Pancreatic+cancer&source=bl&ots=H0iCeaPP0N&sig=pqJT1tPMR6C-NIig3S_NkFKFsD0&hl=en&sa=X&ved=0ahUKEwi4nLrgzuPQAhUUIWMKHS3wBoc4ChDoAQhNMAg#v=onepage&q=connection%20between%20li%20fraumeni%20and%20Pancreatic%20cancer&f=false
  5. Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2013 Apr 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. https://www.ncbi.nlm.nih.gov/pubmed/20301488
  6. Elisa Becze BA, ELS, 2011 Mar 1. An introduction to Li-Fraumeni Syndrome, Five-Minute-In-Service. http://connect.ons.org/columns/five-minute-in-service/an-introduction-to-li-fraumeni-syndrome
  7. Sorrell, A. D., Espenschied, C. R., Culver, J. O., & Weitzel, J. N. (2013).TP53Testing and Li-Fraumeni Syndrome: Current Status of Clinical Applications and Future Directions. Molecular Diagnosis & Therapy17(1), 31–47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627545/
  8. Emily J. Lewis. PRIMA-1 as a cancer therapy restoring mutant p53: a reviewBioscience Horizons (2015) 8: hzv006 http://biohorizons.oxfordjournals.org/content/8/hzv006.full
  9. Izetti, Patricia, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Juliana Giacomazzi, Bárbara Alemar, Guido Lenz, et al. ‘PRIMA-1, a Mutant p53 Reactivator, Induces Apoptosis and Enhances Chemotherapeutic Cytotoxicity in Pancreatic Cancer Cell Lines’. Investigational New Drugs 32, no. 5 (October 2014): 783–94. https://www.ncbi.nlm.nih.gov/pubmed/24838627

Izetti, Patricia, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Juliana Giacomazzi, Bárbara Alemar, Guido Lenz, et al. ‘PRIMA-1, a Mutant p53 Reactivator, Induces Apoptosis and Enhances Chemotherapeutic Cytotoxicity in Pancreatic Cancer Cell Lines’. Investigational New Drugs 32, no. 5 (October 2014): 783–94

Other related articles published in this Online Scientific Journal include the following:

p53 mutation – Li-Fraumeni Syndrome – Likelihood of Genetic or Hereditary conditions playing a role in Intergenerational incidence of Cancer

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/01/p53-mutation-li-fraumeni-syndrome-likelihood-of-genetic-or-hereditary-conditions-playing-a-role-in-intergenerational-incidence-of-cancer/

Pancreatic Cancer: Articles of Note @PharmaceuticalIntelligence.com

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/26/pancreatic-cancer-articles-of-note-pharmaceuticalintelligence-com/

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AstraZeneca’s WEE1 protein inhibitor AZD1775 Shows Success Against Tumors with a SETD2 mutation

Stephen J. Williams, Ph.D., Curator

There have been multiple trials investigating the utility of cyclin inhibitors as anti-tumoral agents (see post) with the idea of blocking mitotic entry however another potential antitumoral mechanism has been to drive the cell into mitosis in the presence of DNA damage or a defective DNA damage repair capacity. A recent trial investigating an inhibitor or the cell cycle checkpoint inhibitor Wee1 showed positive results in select cohorts of patients with mutations in DNA repair, indicating the therapeutic advantage of hijacking the cell’s own DNA damage response, much like how PARP inhibitor Olaparib works in BRCA1 mutation positive ovarian cancer patients.

John Carroll at FierceBiotech reported that an Oxford team spotlights promise of AstraZeneca drug in targeting cancers.

According to his report,

Investigators at Oxford University say that one of AstraZeneca’s ($AZN) pipeline drugs proved particularly effective in killing cancer cells with a particular genetic mutation.

The ex-Merck ($MRK) drug is AstraZeneca’s WEE1 protein inhibitor AZD1775, which proved particularly lethal to genes with a SETD2 mutation, which the researchers see as a potential ‘Achilles heel’ often found in kidney cancer and childhood brain tumors.

“When WEE1 was inhibited in cells with a SETD2 mutation, the levels of deoxynucleotides, the components that make DNA, dropped below the critical level needed for replication,” noted Oxford’s Andy Ryan. “Starved of these building blocks, the cells die. Importantly, normal cells in the body do not have SETD2 mutations, so these effects of WEE1 inhibition are potentially very selective to cancer cells.”

AstraZeneca landed rights to the drug back in 2013, when incoming Merck R&D chief Roger Perlmutter opted to spin it out while focusing an immense effort around the development of its PD-1 checkpoint inhibitor KEYTRUDA® (pembrolizumab)‎. Since then, AstraZeneca has made it available to academic investigators through their open innovation program.

Since picking up the drug, AstraZeneca has posted positive mid-stage data for p53 mutated ovarian cancer at the last big ASCO meeting, (and see associated abstract on Multicenter randomized Phase II study of AZD1775 plus chemotherapy versus chemotherapy alone in patients with platinum-resistant TP53-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer) noting its qualification as a first-in-class player in their pipeline.

Wee1, DNA damage checkpoint and cell cycle regulation

 

In fission yeast, Wee1 delays entry into mitosis by inhibiting the activity of Cdk1, the cyclin-dependent kinase that promotes entry into mitosis (Cdk1 is encoded by the cdc2+ gene in fission yeast and the CDC28 gene in budding yeast) (Russell and Nurse, 1987a). Wee1 inhibits Cdk1 by phosphorylating a highly conserved tyrosine residue at the N-terminus (Featherstone and Russell, 1991; Gould and Nurse, 1989; Lundgren et al., 1991; Parker et al., 1992; Parker and Piwnica-Worms, 1992). The phosphatase Cdc25 promotes entry into mitosis by removing the inhibitory phosphorylation (Dunphy and Kumagai, 1991; Gautier et al., 1991; Kumagai and Dunphy, 1991; Millar et al., 1991; Russell and Nurse, 1986; Strausfeld et al., 1991). Loss of Wee1 activity causes cells to enter mitosis before sufficient growth has occurred and cytokinesis therefore produces two abnormally small daughter cells (Fig. 1A) (Nurse, 1975). Conversely, increasing the gene dosage of wee1 causes delayed entry into mitosis and an increase in cell size, indicating that the levels of Wee1 activity determine the timing of entry into mitosis and can have strong effects on cell size (Russell and Nurse, 1987a). Similarly, cdc25 mutants undergo delayed entry into mitosis, producing abnormally large cells, and an increase in the gene dosage of cdc25 causes premature entry into mitosis and decreased cell size (Russell and Nurse, 1986). Despite these difficulties, early work in fission yeast suggested that the Wee1 kinase plays an important role in a checkpoint that coordinates cell growth and cell division at the G2/M transition (Fantes and Nurse, 1978; Nurse, 1975; Thuriaux et al., 1978). WEE1 is an evolutionarily conserved nuclear tyrosine kinase (Table 2) that is markedly active during the S/G2 phase of the cell cycle [24, 25]. It was first discovered 25 years ago as a cell division cycle (cdc) mutant-wee1– in the fission yeast, Schizosaccharomyces pombe [26]. Fission yeast lacking WEE1 are characterized by a smaller cell size, and this phenotype has been attributed to the ability of WEE1 to negatively regulate the activity of cyclin dependent kinase, Cdc2 (Cdc28 in budding yeast and CDK1 in human), in the Cdc2/CyclinB complex [27]. Recently, WEE1 was shown to directly phosphorylate the mammalian core histone H2B at tyrosine 37 in a cell cycle dependent manner. Inhibition of WEE1 kinase activity either by a specific inhibitor (MK-1775) or suppression of its expression by RNA interference abrogated H2B Y37-phosphorylation with a concurrent increase in histone transcription [17].

 

As shown in the Below figure Wee1 is a CDK cyclin kinase which results in an inactivating phosphorylation event on CDK/Cyclin complexes

CellCycleFig3Wee1Chk1

Figure 1. Schematic representation of the effects of Chk1 and Wee1 inhibition on CDK-CYCLIN complex regulation, that gets more activated being unphosphorylated from Cell cycle, checkpoints and cancer by Laura Carrassa.

CellCycleWee1

Figure 2. Schematic representation of the role of Chk1 and Wee1 in regulation of the CDK-cyclin complexes involved in S phase and M phase entry from Cell cycle, checkpoints and cancer by Laura Carrassa.

The following articles discuss how Wee1 can be a target and synergize with current chemotherapy

Wee1 kinase as a target for cancer therapy

 

Combined inhibition of the cell cycle related proteins Wee1 and Chk1/2 induces synergistic anti-cancer effect in melanoma.

Magnussen GI, Emilsen E, Giller Fleten K, Engesæter B, Nähse-Kumpf V, Fjær R, Slipicevic A, Flørenes VA.

BMC Cancer. 2015 Jun 10;15:462. doi: 10.1186/s12885-015-1474-8.

A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation.

Hatano K, Kumar B, Zhang Y, Coulter JB, Hedayati M, Mears B, Ni X, Kudrolli TA, Chowdhury WH, Rodriguez R, DeWeese TL, Lupold SE.

Nucleic Acids Res. 2015 Apr 30;43(8):4075-86. doi: 10.1093/nar/gkv273. Epub 2015 Apr 6.

 

 

 

p53 mutation Frequency in Ovarian Cancer and contribution to chemo-resistance

The following is from the curated database TCGA and cBioPortal TCGA Data Viewer for mutations found in ovarian cancer sequencing studies in the literature

http://www.cbioportal.org/study.do?cancer_study_id=ov_tcga_pub

According to TCGA researchers have:

  • Confirmed that mutations in gene TP53 are present in more than 96 percent of ovarian cases (>57% mutation frequency) while SETD2 mutations are present in only 1% of cases (1.1% mutation frequency).

In general, ovarian cancers with TP53 are considered to have increased resistance to commonly used cytotoxic agents used for this neoplasm, for example cisplatin and taxol, as TP53 is a major tumor suppressor/transcription factor involved in cell cycle, DNA damage response, and other chemosensitivity mechanisms. One subtype of TP53 mutations, widely termed gain-of-function (GOF) mutations, surprisingly converts this protein from a tumor suppressor to an oncogene. We term the resulting change an oncomorphism. In this review, we discuss particular TP53 mutations, including known oncomorphic properties of the resulting mutant p53 proteins. For example, several different oncomorphic mutations have been reported, but each mutation acts in a distinct manner and has a different effect on tumor progression and chemoresistance.

p53mutonco

Figure 1. The spectrum of protection against cancer provided by WT p53. As copies of WT p53 (TP53+/+) are lost, cancer protection decreases. When oncomorphic mutations are acquired, cancer susceptibility is increased.

Oncomorphic p53 proteins were first identified over two decades ago, when different TP53 mutants were introduced into cells devoid of endogenous p53 [38,39]. Among all cancers, the most common oncomorphic mutations are at positions R248, R273, and R175, and in ovarian cancers the most common oncomorphic TP53 mutations are at positions R273, R248, R175, and Y220 at frequencies of 8.13%, 6.02%, 5.53%, and 3.74%, respectively [33,34]. In in vitro studies, cells with oncomorphic p53 demonstrate increased invasion, migration, angiogenesis, survival, and proliferation as well as resistance to chemotherapy [35,37,40,41].

hotspotsforp53mutations

Figure 2. Hotspots for TP53 mutations. Mutations that occur at a frequency greater than 3% are highlighted. Certain p53 mutants have oncomorphic activity (denoted by *), functioning through novel protein interactions as well as novel transcriptional targets to promote cell survival and potentially chemoresistance. Codons in the “other” category include those that produce non-functional p53 or have not been characterized to date.

Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence.

Osman AA, Monroe MM, Ortega Alves MV, Patel AA, Katsonis P, Fitzgerald AL, Neskey DM, Frederick MJ, Woo SH, Caulin C, Hsu TK, McDonald TO, Kimmel M, Meyn RE, Lichtarge O, Myers JN.

Mol Cancer Ther. 2015 Feb;14(2):608-19. doi: 10.1158/1535-7163.MCT-14-0735-T. Epub 2014 Dec 10.

Mol Cancer Ther. 2015 Jan;14(1):90-100. doi: 10.1158/1535-7163.MCT-14-0496. Epub 2014 Nov 5.

Mol Cancer Ther. 2013 Aug;12(8):1442-52. doi: 10.1158/1535-7163.MCT-13-0025. Epub 2013 May 22.

Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy.

Guertin AD1, Li J, Liu Y, Hurd MS, Schuller AG, Long B, Hirsch HA, Feldman I, Benita Y, Toniatti C, Zawel L, Fawell SE, Gilliland DG, Shumway SD.

The protein phosphatase 2A inhibitor LB100 sensitizes ovarian carcinoma cells to cisplatin-mediated cytotoxicity.

Chang KE1, Wei BR2, Madigan JP1, Hall MD1, Simpson RM2, Zhuang Z3, Gottesman MM4.

Author information

  • 1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  • 2Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  • 3Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
  • 4Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. mgottesman@nih.gov.

Abstract

Despite early positive response to platinum-based chemotherapy, the majority of ovarian carcinomas develop resistance and progress to fatal disease. Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase involved in the regulation of DNA-damage response (DDR) and cell-cycle checkpoint pathways. Recent studies have shown that LB100, a small-molecule inhibitor of PP2A, sensitizes cancer cells to radiation-mediated DNA damage. We hypothesized that LB100 could sensitize ovarian cancer cells to cisplatin treatment. We performed in vitro studies in SKOV-3, OVCAR-8, and PEO1, -4, and -6 ovarian cancer lines to assess cytotoxicity potentiation, cell-death mechanism(s), cell-cycle regulation, and DDR signaling. In vivo studies were conducted in an intraperitoneal metastatic mouse model using SKOV-3/f-Luc cells. LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. Sensitization via LB100 was mediated by abrogation of cell-cycle arrest induced by cisplatin. Loss of the cisplatin-induced checkpoint correlated with decreased Wee1 expression, increased cdc2 activation, and increased mitotic entry (p-histone H3). LB100 also induced constitutive hyperphosphorylation of DDR proteins (BRCA1, Chk2, and γH2AX), altered the chronology and persistence of JNK activation, and modulated the expression of 14-3-3 binding sites. In vivo, cisplatin sensitization via LB100 significantly enhanced tumor growth inhibition and prevented disease progression after treatment cessation. Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DDR pathway and cell-cycle checkpoint abrogation.

 

So Why SETD2 Mutations?

SETD2 is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin and chromatin remodeling.

Evidences for mutations in the histone modifying gene SETD2 as critical drivers in leukemia development. Wang Q, et al. Sci China Life Sci, 2014 Sep. PMID 25077743

SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.

Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrík M, Rowan AJ, Patel H, Rabinowitz A, East P, Wilson G, Santos CR, McGranahan N, Gulati S, Gerlinger M, Birkbak NJ, Joshi T, Alexandrov LB, Stratton MR, Powles T, Matthews N, Bates PA, Stewart A, Szallasi Z, Larkin J, Bartek J, Swanton C.

Oncogene. 2015 Mar 2. doi: 10.1038/onc.2015.24. [Epub ahead of print]

PMID:

 

Microsatellite instability: an update.

Yamamoto H, Imai K.

Arch Toxicol. 2015 Jun;89(6):899-921. doi: 10.1007/s00204-015-1474-0. Epub 2015 Feb 22.

PMID:

25701956

Similar articles

Select item 255282163.

Loss of MLH1 confers resistance to PI3Kβ inhibitors in renal clear cell carcinoma with SETD2 mutation.

Feng C, Ding G, Jiang H, Ding Q, Wen H.

Tumour Biol. 2015 May;36(5):3457-64. doi: 10.1007/s13277-014-2981-y. Epub 2014 Dec 21.

PMID:

25528216

Similar articles

Select item 249316104.

SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.

Pfister SX, Ahrabi S, Zalmas LP, Sarkar S, Aymard F, Bachrati CZ, Helleday T, Legube G, La Thangue NB, Porter AC, Humphrey TC.

Cell Rep. 2014 Jun 26;7(6):2006-18. doi: 10.1016/j.celrep.2014.05.026. Epub 2014 Jun 12.

PMID:

24931610

Free PMC Article

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Select item 248430025.

SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint.

Carvalho S, Vítor AC, Sridhara SC, Martins FB, Raposo AC, Desterro JM, Ferreira J, de Almeida SF.

Elife. 2014 May 6;3:e02482. doi: 10.7554/eLife.02482.

PMID:

24843002

Free PMC Article

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Select item 245764046.

Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers. (NOTE did this as post before)

Ahn JW, Kim HS, Yoon JK, Jang H, Han SM, Eun S, Shim HS, Kim HJ, Kim DJ, Lee JG, Lee CY, Bae MK, Chung KY, Jung JY, Kim EY, Kim SK, Chang J, Kim HR, Kim JH, Lee MG, Cho BC, Lee JH, Bang D.

Genome Med. 2014 Feb 27;6(2):18. doi: 10.1186/gm535. eCollection 2014.

PMID:

24576404

 

The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα.

Li F, Mao G, Tong D, Huang J, Gu L, Yang W, Li GM.

Cell. 2013 Apr 25;153(3):590-600. doi: 10.1016/j.cell.2013.03.025.

PMID:

23622243

Free PMC Article

 

Active NCI Clinical Trials of MK-1775 for Solid Tumors

 

NOTE Four Clinical Trials Investigating Mk-1775 and TP53 Status

1 Recruiting A Study of AZD1775 + Chemotherapy Versus Chemotherapy in Patients to Treat Ovarian, Fallopian Tube, Peritoneal Cancer.

Condition: Ovarian, Fallopian Tube, Peritoneal Cancer,

P53 Mutation

Intervention: Drug: AZD1775
2 Recruiting Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Conditions: Malignant Ovarian Mixed Epithelial Tumor;   Ovarian Brenner Tumor;   Ovarian Carcinosarcoma;   Ovarian Clear Cell Cystadenocarcinoma;   Ovarian Endometrioid Adenocarcinoma;   Ovarian Mucinous Cystadenocarcinoma;   Ovarian Serous Cystadenocarcinoma;   Ovarian Serous Surface Papillary Adenocarcinoma;   Recurrent Fallopian Tube Carcinoma;   Recurrent Ovarian Carcinoma;   Recurrent Primary Peritoneal Carcinoma;   Undifferentiated Ovarian Carcinoma
Interventions: Drug: Gemcitabine Hydrochloride;   Other: Laboratory Biomarker Analysis;   Other: Pharmacological Study;   Other: Placebo;   Drug: WEE1 Inhibitor AZD1775
3 Active, not recruiting A Study of MK-1775 in Combination With Paclitaxel and Carboplatin Versus Paclitaxel and Carboplatin Alone for Participants With Platinum-Sensitive Ovarian Tumors With the P53 Gene Mutation (MK-1775-004)

Condition: Ovarian Cancer
Interventions: Drug: MK1775;   Drug: Placebo;   Drug: paclitaxel;

Drug: carboplatin

4 Not yet recruiting Phase II, Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients

Condition: Small Cell Lung Cancer
Intervention: Drug: AZD1775

 

#2. Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

This study is currently recruiting participants. (see Contacts and Locations)

ClinicalTrials.gov Identifier: NCT02101775

Purpose

This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of time. Gemcitabine hydrochloride may prevent tumor cells from multiplying by damaging their deoxyribonucleic acid (DNA, molecules that contain instructions for the proper development and functioning of cells), which in turn stops the tumor from growing. The protein WEE1 may help to repair the damaged tumor cells, so the tumor continues to grow. WEE1 inhibitor MK-1775 may block the WEE1 protein activity and may increase the effectiveness of gemcitabine hydrochloride by preventing the WEE1 protein from repairing damaged tumor cells without causing harm to normal cells. It is not yet known whether gemcitabine hydrochloride with or without WEE1 inhibitor MK-1775 may be an effective treatment for recurrent ovarian, primary peritoneal, or fallopian tube cancer.

Primary Outcome Measures:

  • PFS evaluated using RECIST version 1.1 [ Time Frame: Time from start of treatment to time to progression or death, whichever occurs first, assessed up to 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • GCIG CA125 response rate [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Incidence of grade 3 or 4 serious adverse events, graded according to the National Cancer Institute CTCAE version 4.0 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
  • Objective response by RECIST version 1.1 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]

Survival estimates will be computed using the Kaplan-Meier method.

  • p53 protein expression in archival tumor tissue by immunohistochemistry (IHC) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • TP53 mutations (presence and type of mutation) by Sanger sequencing [ Time Frame: Baseline ] [ Designated as safety issue: No ]

 

These Trials Are Not Investigating TP53 Status of Patient Cohorts

A Phase I Study of Single-agent MK-1775, a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors

 

This study is currently recruiting participants. (see Contacts and Locations)

ClinicalTrials.gov Identifier:NCT01748825

 

PRIMARY OBJECTIVE:

  • To establish the safety and tolerability of single-agent MK-1775 in patients with refractory solid tumors
  • To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors

SECONDARY OBJECTIVES:

  • To determine the effect of MK-1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells
  • To evaluate the antitumor activity of MK-1775 in patients with refractory solid tumors

Note: A further expansion cohort of 6 additional patients with documented tumors harboring BRCA-1 or -2 mutations will lso be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population

A Phase 1/2 Study of AZD1775 (MK-1775) in Combination With Oral Irinotecan in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Tumors

PRIMARY OBJECTIVES:

  1. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of MK-1775 (WEE1 inhibitor MK-1775) administered on days 1 through 5 every 21 days, in combination with oral irinotecan (irinotecan hydrochloride), to children with recurrent or refractory solid tumors.
  2. To define and describe the toxicities of MK-1775 in combination with oral irinotecan administered on this schedule.

III. To characterize the pharmacokinetics of MK-1775 in children with refractory cancer.

SECONDARY OBJECTIVES:

  1. To preliminarily define the antitumor activity of MK-1775 and irinotecan within the confines of a Phase 1 study.
  2. To obtain initial Phase 2 efficacy data on the anti-tumor activity of MK-1775 in combination with irinotecan administered to children with relapsed or refractory neuroblastoma and in children with relapsed or refractory medulloblastoma/CNS PNET (central nervous system primitive neuroectodermal tumor).

III. To investigate checkpoint over-ride by MK-1775 via the mechanism-based pharmacodynamic (PD) biomarker of decreased cyclin-dependent kinase 1 (CDK1) phosphorylation in correlative and exploratory studies.

  1. To evaluate potential predictive biomarkers of MK-1775 sensitivity, including v-myc avian myelocytomatosis viral oncogene homolog (MYC), v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), phosphorylated-WEE1 G2 checkpoint kinase (p-Wee1), enhancer of zeste homolog 2 (Drosophila) (EZH2) and gamma-H2A histone family, member X (H2AX) in tumor tissues in correlative and exploratory studies.

 

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Personalized Medicine and Colon Cancer

Author: Tilda Barliya, PhD

According to Dr. Neil Risch a leading expert in statistical genetics and the director of the UCSF Institute for Human Genetics,  “Personalized medicine, in which a suite of molecules measured in a patient’s lab tests can inform decisions about preventing or treating diseases, is becoming a reality” (7).

Colorectal cancer (CRC) is the third most common cancer and the fourth-leading cause of cancer death worldwide despite advances in screening, diagnosis, and treatment. Staging is the only prognostic classification used in clinical practice to select patients for adjuvant chemotherapy. However, pathological staging fails to predict recurrence accurately in many patients undergoing curative surgery for localized CRC (1,2). Most of the patients who are not eligible for surgery need adjuvant chemotherapy in order to avoid relapse or to increase survival. Unfortunately, only a small portion of them shows an objective response to chemotherapy, becoming problematic to correctly predict patients’ clinical outcome (3).

CRC patients are normally being tested for several known biomarkers which falls into 4 main categories (5):

  1. Chromosomal Instability (CIN)
  2. Microsatellite Instability (MSI)
  3. CpG Island methylator phynotype (CIMP)
  4. Global DNA hypomethylation

In the past few years many studies have exploited microarray technology to investigate gene expression profiles (GEPs) in CRC, but no established signature has been found that is useful for clinical practice, especially for predicting prognosis.  Only a subset of CRC patients with MSI tumors have been shown to have better prognosis and probably respond differently to adjuvant chemotherapy compared to microsatellite stable (MSS) cancer patients (6).

Pritchard & Grady have summarized the selected biomarkers that have been evaluated in colon cancer patients (10).

Table 1

Selected Biomarkers That Have Been Evaluated in Colorectal Cancer

Biomarker Molecular Lesion Frequency
in CRC
Prediction Prognosis Diagnosis
KRAS Codon 12/13 activating
mutations; rarely codon
61, 117,146
40% Yes Possible
BRAF V600E activating
mutation
10% Probable Probable Lynch
Syndrome
PIK3CA Helical and kinase
domain mutations
20% Possible Possible
PTEN Loss of protein by IHC 30% Possible
Microsatellite Instability (MSI) Defined as >30%
unstable loci in the NCI
consensus panel or
>40% unstable loci in a
panel of mononucleotide
microsatellite repeats9
15% Probable Yes Lynch
Syndrome
Chromosome Instability (CIN) Aneuploidy 70% Probable Yes
18qLOH Deletion of the long arm
of chromosome 18
50% Probable Probable
CpG Island Methylator
Phenotype (CIMP)
Methylation of at least
three loci from a selected
panel of five markers
15% +/− +/−
Vimentin (VIM) Methylation 75% Early
Detection
TGFBR2 Inactivating Mutations 30%
TP53 Mutations Inactivating Mutations 50%
APC Mutations Inactivating Mutations 70% FAP
CTNNB1 (β-Catenin) Activating Mutations 2%
Mismatch Repair Genes Loss of protein by IHC;
methylation; inactivating
mutations
1–15% Lynch
Syndrome

CRC- colorectal cancer; IHC- immunohistochemistry; FAP- Familial Adenomatous Polyposis

Examples for the great need of personalized medicine tailored according to the patients’ genetics is clearly seen with two specific drugs for CRC:  Cetuximab and panitumumab are two antibodies that were developed to treat colon cancer. However, at first it seemed as if they were a failure because they did not work in many patients. Then, it was discovered that if a cancer cell has a specific genetic mutation, known as K-ras, these drugs do not work.  This is an excellent example of using individual tumor genetics to predict whether or not treatment will work (8).

According to Marisa L et al, however, the molecular classification of CC currently used, which is based on a few common DNA markers as mentioned above (MSI, CpG island methylator phenotype [CIMP], chromosomal instability [CIN], and BRAF and KRAS mutations), needs to be refined.

Genetic Expression Profiles (GEP)

CRC is composed of distinct molecular entities that may develop through multiple pathways on the basis of different molecular features, as a consequence, there may be several prognostic signatures for CRC, each corresponding to a different entity. GEP studies have recently identified at least three distinct molecular subtypes of CC (4). Dr. Marisa Laetitia and her colleagues from the Boige’s lab however, have conducted a very thorough study and identifies 6 distinct clusters for CC patients. Herein, we’ll describe the majority of this study and their results.

Study  Design:

Marisa L et al (1) performed a consensus unsupervised analysis (using an Affymertix chip) of the GEP on tumor tissue sample from 750 patients with stage I to IV CC. Patients were staged according to the American Joint Committee on Cancer tumor node metastasis (TNM) staging system. Of the 750 tumor samples of the CIT cohort, 566 fulfilled RNA quality requirements for GEP analysis. The 566 samples were split into a discovery set (n = 443) and a validation set (n = 123).

Several known mutations were used as internal controls, including:

  • The seven most frequent mutations in codons 12 and 13 of KRAS .
  • The BRAF c.1799T>A (p.V600E)
  • TP53mutations (exons 4–9)
  • MSI was analyzed using a panel of five different microsatellite loci from the Bethesda reference panel
  • CIMP status was determined using a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1)

Results:

The results revealed six clusters of samples based on the most variant probe sets. The consensus matrix showed that C2, C3, C4, and C6 appeared as well-individualized clusters, whereas there was more classification overlap between C1 and C5. In other words:

  • Tumors classified as C1, C5, and C6 were more frequently CIN+, CIMP−TP53 mutant, and distal (p<0.001), without any other molecular or clinicopathological features able to discriminate these three clusters clearly.
  • Tumors classified as C2, C4, and C3 were more frequently CIMP+ (59%, 34%, and 18%, respectively, versus <5% in other clusters) and proximal.
  • C2 was enriched for dMMR (68%) and BRAF- mutant tumors (40%).
  • C3 was enriched for KRAS- mutant tumors (87%).

Note: No association between clusters and TNM stage (histopathology) was found, except enrichment for metastatic (31%) tumors in C4.

Figure: These signaling pathways associated with the molecular subtype (by cluster)

Figure 2 Signaling pathways associated with each molecular subtype.

Marisa L et al. Signaling pathways associated with each molecular subtype

These clusters fall into several signaling pathways:

  • up-regulated immune system and cell growth pathways were found in C2, the subtype enriched for dMMR tumors
  • C4 and C6 both showed down-regulation of cell growth and death pathways and up-regulation of the epithelial–mesenchymal transition/motility pathways. displaying “stem cell phenotype–like” GEPs (91%)
  • Most signaling pathways were down-regulated in C1 and C3.
  • In C1, cell communication and immune pathways were down-regulated.
  • In C5, cell communication, Wnt, and metabolism pathways were up-regulated.

These results are further summarized in table 2:

Figure 3 Summary of the main characteristics of the six subtypes.

Marisa L et al. Gene Expression Classification of Colon Cancer into Molecular Subtypes

The authors have identified six robust molecular subtypes of CC individualized by distinct clinicobiological characteristics (as summarized in table 2).

This classification successfully identified the dMMR tumor subtype, and also individualized five other distinct subtypes among pMMR tumors, including three CIN+ CIMP− subtypes representing slightly more than half of the tumors. As expected, mutation of BRAF was associated with the dMMR subtype, but was also frequent in the C4 CIMP+ poor prognosis subtype. TP53– andKRAS-mutant tumors were found in all the subtypes; nevertheless, the C3 subtype, highly enriched in KRAS-mutant CC, was individualized and validated, suggesting a specific role of this mutation in this particular subgroup of CC.

Current Treatments for colon cancer- Table 3 (11) .

Constant S et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Exploratory analysis of each subtype GEP with previously published supervised signatures and relevant deregulated signaling pathways improved the biological relevance of the classification.

The biological relevance of our subtypes was highlighted by significant differences in prognosis. In our unsupervised hierarchical clustering, patients whose tumors were classified as C4 or C6 had poorer RFS than the other patients.

Prognostic analyses based solely on common DNA alterations can distinguish between risk groups, but are still inadequate, as most CCs are pMMR CIMP− BRAFwt.

The markers BRAF-mutant, CIMP+, and dMMR may be useful for classifying a small proportion of cases, but are uninformative for a large number of patients.

Unfortunately, 5 of the 9 anti-CRC drugs approved by the FDA today are basic cytotoxic chemotherapeutics that attack cancer cells at a very fundamental level (i.e. the cell division machinery) without specific targets, resulting in poor effectiveness and strong side-effects (Table 3) (11).

An example for side effects induction mechanisms have also been reported in CRC for the BRAF(V600E) inhibitor Vemurafenib that triggers paradoxical EGFR activation (12).

Summary:

The authors of this study “report a new classification of CC into six robust molecular subtypes that arise through distinct biological pathways and represent novel prognostic subgroups. Our study clearly demonstrates that these gene signatures reflect the molecular heterogeneity of CC. This classification therefore provides a basis for the rational design of robust prognostic signatures for stage II–III CC and for identifying specific, potentially targetable markers for the different subtypes”.

These results further underline the urgent need to expand the standard therapy options by turning to more focused therapeutic strategies: a targeted therapy-for specific subtype profile.. Accordingly, the expansion and the development of new path of therapy, like drugs specifically targeting the self-renewal of intestinal cancer stem cells – a tumor cell population from which CRC is supposed to relapse, remains relevant.

Therefore, the complexity of these results supports the arrival of a personalized medicine, where a careful profiling of tumors will be useful to stratify patient population in order to test drugs sensitivity and combination with the ultimate goal to make treatments safer and more effective.

References:

1. Marisa L,  de Reyniès A, Alex Duval A,  Selves J, Pierre Gaub M, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Fléjou JF…Boige V. Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value. PLoS Med May 2013 10(5): e1001453. doi:10.1371. http://www.plosmedicine.org/article/info%3Adoi/10.1371/journal.pmed.1001453

2. Villamil BP, Lopez AR, Prieto SH, Campos GL, Calles A, Lopez- Asenjo JA, Sanz Ortega J, Perez CF, Sastre J, Alfonso R, Caldes T, Sanchez FM and Rubio ED. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 2012, 12:260.  http://www.biomedcentral.com/1471-2407/12/260/

3. Diaz-Rubio E, Tabernero J, Gomez-Espana A, Massuti B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, et al.: Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 2007, 25(27):4224-4230. http://jco.ascopubs.org/content/25/27/4224.long

4. Salazar R, Roepman P, Capella G, Moreno V, Simon I, et al. (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29: 17–24. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Salazar%5Bauthor%5D%20AND%20Gene%20expression%20signature%20to%20improve%20prognosis%20prediction%20of%20stage%20II%20and%20III%20colorectal%20cancer

5.  By: Global Genome Knowledge. Colorectal Cancer- Personalized Medicine, Now a Clinical Reality.  http://www.srlworld.com/innersense/Voice-135-Colorectal-Cancer-Sept-2012-IS.pdf

6. Popat S, Hubner R and Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005 Jan 20;23(3):609-618. http://www.ncbi.nlm.nih.gov/pubmed/15659508

7. By: Jeffrey Norris. Value of Genomics and Personalized Medicine Is Wrongly Downplayed.http://www.ucsf.edu/news/2012/04/11864/value-genomics-and-personalized-medicine-wrongly-downplayed

8. By: James C Salwitz. The Future is now: Personalized Medicine. http://www.cancer.org/cancer/news/expertvoices/post/2012/04/18/the-future-is-now-personalized-medicine.aspx

9. Jeffrey A. Meyerhardt., and Robert J. Mayer. Systemic Therapy for Colorectal Cancer. N Engl J Med 2005;352:476-487. http://www.med.upenn.edu/gastro/documents/NEJMchemotherapycolorectalcancer.pdf

10. Pritchard CC and Grady WM. Colorectal Cancer Molecular Biology Moves Into Clinical Practice. Gut. Jan 2011 60(1): 116-129.  Gut. 2011 January; 60(1): 116–129http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006043/

11. Constant S, Huang S, Wiszniewski L andMas C. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies.  Pharmacology, Toxicology and Pharmaceutical Science » “Drug Discovery”, book edited by Hany A. El-Shemy, ISBN 978-953-51-0906-8.  http://www.intechopen.com/books/drug-discovery/colon-cancer-current-treatments-and-preclinical-models-for-the-discovery-and-development-of-new-ther

12. Prahallad, C. Sun, S. Huang, F. Di Nicolantonio, R. Salazar, D. Zecchin, R. L. Beijersbergen, A. Bardelli, R. Bernards, 2012 Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature Jan 2012 483 (7387): 100-103. http://www.nature.com/nature/journal/v483/n7387/full/nature10868.html

Other related articles on this Open Access Online Scientific Journal include the following:

*. By Tilda Barliya PhD. Colon Cancer. https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

**. By: Tilda Barliya PhD. CD47: Target Therapy for Cancer. https://pharmaceuticalintelligence.com/2013/05/07/cd47-target-therapy-for-cancer/

I. By: Aviva Lev-Ari, PhD, RNCancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. https://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. https://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.DIssues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.DIn Focus: Targeting of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. https://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. https://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

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