Oct 30, 2014

2014年10月30日癌症研究國際研討會: 從基礎科學到臨床應用

2014年10月30日癌症研究國際研討會: 從基礎科學到臨床應用

由 sufang 在 四, 10/30/2014 - 09:42 發表 
首頁: http://scr.nhri.org.tw/index.jsp
台大醫院國際會議中心 301會議室 (77240109)
衛福部 許明能次長致辭
龔院長致辭

1. 張元吉教授: Combination targeted therapy in advanced lung cancer

2. 陳慶士教授: Fighting an organized crime network in pancreatic cancer: tumor and its microenvironment

3. 馮新華教授: How cancer cells escape from TGF-b control?

4. 安康教授: From nutrient deficiency to mitochondria dysfunction: a translational study of targeting arginine auxotrophic cancers

5. 楊慕華教授: The two sided effect of snail in cancer metastasis

6. 洪明奇院士: Mechanism-driven target therapy

7. 閻雲校長: Nanoparticles conjugated shRNA in cancer therapy

8. 麥德華教授: Future anti-cancer targets: put the cart before the horses?

9. 葉祥勝博士: Pre-competitive collaborations to promote cancer reasearch and drug development in Asia

10. 侯明峰教授: The role of adipocytokines in breast cancer

11. 王陸海院士: Glucocorticoids mediated induction of miRNA-708 to suppress ovarian cancer cell invasion and metastasis through targeting Rap18

Round Table Duscussion:
  • different phenotype of cancer cells in cancer tissues (hypoxia, nutrient)
  • combination therapies, modality
  • pharmatheutical company working model (team work)
  • Kung asked Mak: metabolic stress based therapies: (a) IDH1 therpey is very stunning. change the environment of cancer TME, instead of killing them. Ser/Gly/Glu are essential in cancer cells but not essential for normal cells (b) immuno cancer therapy, a small step a time
  • Yen Yun: (a) before jumping into drug development, (a) work with a good drug team (b) informatics (literature and database)-guided
  • 葉祥勝: hope PDX can predicts better for human cancer response
  • Leo Chen to 紀雅惠: Umbrella design.
10/31 Mini-symposium at NHRI
10/30/2014
Asia/Taipei

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‹ Tak Wah MakEBV associated malignancies and IDO1 expression ›
#1由 sufang 在 六, 11/01/2014 - 14:24 發表。

王陸海院士: Glucocorticoids mediated induction of miRNA-708

王陸海院士: Glucocorticoids mediated induction of miRNA-708 to suppress ovarian cancer cell invasion and metastasis through targeting Rap18
  • In vitro then in vivo selection of invasive ovarian cancer cells -SKOV-16.
  • miRNA-708 is down-regulated in metastatic ovarian epitelial cancer cells.
#2由 sufang 在 六, 11/01/2014 - 14:22 發表。

侯明峰教授: The role of adipocytokines in breast cancer

侯明峰教授: Kaohsiung Municipal Ta-Tung Hospital/Kaohsiung Medical University (高雄市立大同醫院/高雄醫學大學)
  • Overall survival of breast cancer
  • Obseity related diseases
  • adipocytokinase comprise a variety of proteins including resistin, vesfatin
  • Implicaitonof resistin in different pathogenesis
  • Incrased resistin and its association wiht positiv ER status in breast cancer in Taiwan
  • Vesfatin (an enzyme, NAD dep-pathway, ... altered vesfatin is a poor prognosis of breast caner m 似乎與ER/PGR有關係)
  • Serum resistin and vesfatin : higher in breast cancer patients than those in healthy patients.
  • Biology study: (a) visfatin promoted brest cancer cell growth (b) FK866 is Visfastin inhibitor (c) visfastin promotes MDA-MB231 metastasis in zebra fish. (d) Rsistin incrased wound healing assay (e) future direction: involvement of visfatin and vesfatin in EMT
#3由 sufang 在 六, 11/01/2014 - 14:17 發表。

葉祥勝博士: Pre-competitive collaborations to promote cancer

葉祥勝博士: Dr. Xiang S. Ye, Senior Director of Cancer Research in China/Asia, Lilly China Research and Development Center, PRC
 
Pre-competitive collaborations to promote cancer reasearch and drug development in asia
  • Cancers are complex and heterogeneous diseases
  • Genetic diversity
  • The uniqe profile of cancers in China
  • High incidence of EGFR-mutations in China lung cancer
    • cancer genetics define patient tailoring
    • collaboration dn partnership (more targeted therapies)
    • A global open R&D innovation ecosystem
  • Asian cancer reserach group (http://www.asiancancerresearchgroup.org/)
    • ACRG pre-competitive reserach
    • HCC
    • Gastric cancer
    • Lung adenocarcinoma (KRAS mutation, gene fusion..)
    • Publications Nature Genetics 44: July 2012; Genome Research 23 (9) Sep 2013
  • Tumor Bank Consortium Asia: a private and public partnership to advance tailored therpaeutics to Chinese cancer patuents
    • 294 northern chinese patients PNAS under review
  • Molecular annotated PDX identifies HER2 as therapeutic targets in cetuximab-resistance CRO
    • uncoordinated and fragmented effors for genomic
    • THe solutionL pre-competitive PDX consortium
    • PDX consrotiium 2014 funded by 3 founding pjarma platforms
#4由 sufang 在 六, 11/01/2014 - 11:07 發表。

麥德華教授 Future anti-cancer targets: put the cart before the horses

麥德華教授: Dr. Tak Wah Mak, Dept Medical Biophysics, U of Toronto, Canda
  • Today's cancer targets: shoot the horses (=oncogenes) (few recurrent oncogenes, most are tumor suppressor genes, 12 pathways are interwined).
  • The cart is the transformed state of the cancer cell as a consequence of the actions of oncogenes and tumour suppressor genes
  • Future: targeting the carts (=immune/aneuploidy/metabolism)

Immune

-CTLA4, PD-1 etc are immune checkpoints, which lead to landmark paper of NEJM 2010 Improved survival with ipilimumab in patients with metastatic melanoma.

Aneuploidy

TTK and PLK4
-PLK4 centriole duplication CFI-400945
-CFI-400945 in a breast caner PDX
TTK spindle assembly checkpoint

Metabolism

Redox

Inducers and scavengers of ROS (fire and water)
Oncogenes inudce a lot of ROS
Scagengers: Glutathione NADPH, NRF2
De novo GSH synthesis
–Cell Death Differ (2013). Functional significance of glutamate-cysteine ligase modifier for erythrocyte survival in vitro and in vivo.
–GCLM reuired for mammary development (Cancer Cell inpress)
Are tumors addicted to oncogenes or metabolism?
(B) CPT1C (in collaboration with AVEO): Genes Dev (2011). Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.   Redox is crucial to tumor cell survival!!
Nat Rev Cancer (2011) Regulation of cancer cell metabolism.
Multiple molecular mechanisms, both intrinsic and extrinsic, converge to alter core cellular metabolism and provide support for the three basic needs of dividing cells:
(1) rapid ATP generation to maintain energy status (more ATP);
(2) increased biosynthesis of macromolecules (more building blocks);
(3) tightened maintenance of appropriate cellular redox status (more redox).
Three pathways (PPP, IDHs and ME1) for NAPDH and one pathway (glutaminolysis) for GSH.
Figure 4 | Mechanisms of redox control and their alterations in cancer. The production of two of the most abundant antioxidants, reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), has been shown to be modulated in cancers. Pyruvate kinase isoform M2 (PKM2), which is overexpressed in many cancer cells, can divert metabolic precursors away from glycolysis and into the pentose phosphate pathway (PPP) to produce NADPH. NADP-dependent isocitrate dehydrogenase 1 (IDH1), IDH2 and malic enzyme 1 (ME1) also contribute to NADPH production. MYC increases glutamine uptake and glutaminolysis, driving the de novo synthesis of GSH. Additionally, MYC contributes to NADPH production by promoting the expression of PKM2. Together, NADPH and GSH control increased levels of reactive oxygen species (ROS) driven by increased cancer cell proliferation. αKG, α-ketoglutarate; G6P, glucose-6-phosphate.

Cancer Discovery (2013). Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities.

Nat Rev Drug Discov 2013: Modulation of oxidative stress as an anticancer strategy.

Figure 1. The production of reactive oxygen species (ROS) can be induced by hypoxia, metabolic defects, endoplasmic reticulum (ER) stress and oncogenes. Conversely, ROS are eliminated by the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the production of glutathione and NADPH, the activity of tumour suppressors (such as breast cancer susceptibility 1 (BRCA1), p53, phosphatase and tensin homolog (PTEN) and ataxia telangiectasia mutated (ATM)) and the action of dietary antioxidants.

 

 

 

 

 

Figure 2: NRF2 as the master regulator of antioxidant responses. Nuclear factor erythroid 2-related factor 2 (NRF2) controls several different antioxidants pathways. The first is glutathione (GSH) production and regeneration, which is regulated by the following antioxidants: the glutamate–cysteine ligase complex modifier subunit (GCLM), the GCL catalytic subunit (GCLC), the cystine/glutamate transporter XCT and glutathione reductase (GSR). The second is GSH utilization, which is regulated by the glutathione S-transferases (GSTA1, GSTA2, GSTA3, GSTA5, GSTM1, GSTM2, GSTM3 and GSTP1) and glutathione peroxidase 2 (GPX2). The third is thioredoxin (TXN) production, regeneration and ultilization, which is regulated by TXN1, thioredoxin reductase 1 (TXNRD1) and peroxiredoxin 1 (PRDX1). The fourth is NADPH production, which is controlled by glucose-6-phosphate dehydrogenase (G6PD), phosphoglycerate dehydrogenase (PHGDH), malic enzyme 1 (ME1) and isocitrate dehydrogenase 1 (IDH1). Both GSH and TXN utilize NADPH to regenerate themselves once they have reduced reactive oxygen species (ROS). These four groups of antioxidant genes — which are all upregulated by NRF2 — have both complementary and overlapping functions. Additional antioxidants that are controlled by NRF2 include NAD(P)H:quinone oxidoreductase 1 (NQO1) and enzymes regulating iron sequestration, such as haem oxygenase (HMOX1), ferritin heavy chain (FTH) and ferritin light chain (FTL)gure 3: NRF2, p53 and FOXOs support complementary antioxidant pathways. Whereas nuclear factor erythroid 2-related factor 2 (NRF2) mainly affects reduced glutathione (GSH)- and NADPH-related responses, forkead box O (FOXO) proteins and the tumour suppressor p53 regulate superoxide dismutases (SODs), catalase, PTEN-induced putative kinase 1 (PINK1) and sestrins. p53 promotes glutaminolysis via glutaminase 2 (GLS2), which produces the glutamate required for GSH synthesis. In addition, both FOXOs and p53 control NRF2 via the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A). NRF2 activity is also controlled positively by breast cancer susceptibility 1 (BRCA1) and negatively by fumarate hydratase (FH). Notably,several NRF2 target genes have not been included in this figure because they do not pertain to antioxidant functions.

Figure 3: NRF2, p53 and FOXOs support complementary antioxidant pathways. Whereas nuclear factor erythroid 2-related factor 2 (NRF2) mainly affects reduced glutathione (GSH)- and NADPH-related responses, forkead box O (FOXO) proteins and the tumour suppressor p53 regulate superoxide dismutases (SODs), catalase, PTEN-induced putative kinase 1 (PINK1) and sestrins. p53 promotes glutaminolysis via glutaminase 2 (GLS2), which produces the glutamate required for GSH synthesis. In addition, both FOXOs and p53 control NRF2 via the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A). NRF2 activity is also controlled positively by breast cancer susceptibility 1 (BRCA1) and negatively by fumarate hydratase (FH).

 

 

 

 

–Can the regulation of the ROS levels explain BRCA1 carriers mainly only develop breast and ovarian cancers.
–Estrogen-controlled NRF2 activation in BRCA1-related tumorigenesis
–Basal-like breast cancers express lower levels of rearrangements
 
(A) Model for NRF2 regulation in BRCA1-associated tumorigenesis. In breast tissue, estrogen induces NRF2 activation through the PI3K/AKT pathway in BRCA1-deficient cells and protects them from ROS-induced cell death. (B) Major estrogen sources in humans and mice. Red arrow indicates major tissue source of estrogen in premenopausal women. (C) Paracrine signaling in the mammary gland. In response to estrogen and progesterone, paracrine mediators promote the proliferation and differentiation of stem/progenitor cells, as well as ERα-/PR-negative luminal epithelial cells.
#5由 sufang 在 六, 11/01/2014 - 10:41 發表。

閻雲校長:Nanoparticles conjugated shRNA in cancer therapy

閻雲校長: Dr. Yun Yen, Taipei Medical University Nanoparticles conjugated shRNA in cancer therapy
  • Background of ribonucleotide reductase (RR): de-O ribose to deoxyribose
  • HU blocks RR, dNTP pool in leukemia
  • Sequence sepcific inhbiton by GTI-2040 (Northern blot analysis shows greated than 80% decrase in R2); anti-sense of RR
  • Nanoparticles: revolution drug delivery system
  • The poteintial RNAi "short cut"
  • RNA sequence optimization L lead caniddate knocks down target in mice
  • extent and duraton of RRM2 knockdown via siR2B+5
  • siR2B+5 achieves target knowckdown in vivo (CALAA-01)
#6由 sufang 在 六, 11/01/2014 - 10:38 發表。

洪明奇院士: Mechanism-driven target therapy

洪明奇院士: Dr. Mien-Chie Hung, Dept Mol Cell Oncology, U of Texas M.D. Anderson Cancer Center, USA
  • Hh cross talk wiht mTOR/S6K Hh; inhibitor was approved for basal cell carcinoma by FDA in 2012.
  • TNFa/S6K1 phosphorylates Glii1 at S84, which promotes tumorigenesis in vivo.
  • In vivo combination therap of subcutaneously inoculated EAC tumors using GDC-0449 and RA001.
  • Signal crosstalk predics resistance to target therapy and provides biomarkers to stratify patients fo rreadiotherapy.
  • EGFR traget therapy in cancer controversial issue? (gefitinib monotherapy, no improvement in response rate in breast cancer.; adding cetuximab to carboplatn did not improve purcome in breast caner
  • Cross talk between R1175 methylation and Y1173 phophory;aiton negarively modulates EGFR-mediated ERK activation. J Hsu et al, Nat Cell Biology
  • Arginine methylation in the extracellular domain of EGFR
    • PRMT1 interacts with EGFR and methylates EGFR extracellular domain at Arg198 and arg200 Laio et  al Cancer Cell (in revision)
    • higher EGFR methylation is correlated wiht higher recurrence rate after cetuximab treatement and methylEGFR level positively correlated wiht PRMT1 expression
    • Clinical implications: (a) high percentage of arginine methylaton of EGFR
  • Non-canonical functinos of EGFR (a) kinase-independent association wiht sodium/glucose cotransporter (b) locatin -specific functons of EGFR (nucleus, mitochondria/late-endosomes and etc (c) Directly involved in regulaiton of transcription, DNA repair and synthesis, chromatin odifying enxymes and more to be identified.
    • EGFR modulates miRNA maturation in response to hypoxia through phosphorylation of Ago2: Hypoxia -> EGFR/Ago2 -> Ago2-Y393-P --| Ago2/Dicer/TRBP ->maturation of a subset of TS-like miRNA wiht long loop.
#7由 sufang 在 六, 11/01/2014 - 10:19 發表。

楊慕華教授: The two sided effect of snail in cancer metastasis

楊慕華教授 (Dr. Muh-Hwa Yang): The two sided effect of snail in cancer metastasis
Nat Cell Biol. 2014 Mar;16(3):268-80. doi: 10.1038/ncb2910.
MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells.
Hwang WL, Jiang JK, Yang SH, Huang TS, Lan HY, Teng HW, Yang CY, Tsai YP, Lin CH, Wang HW, Yang MH.
Abstract
Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. In cancer cells, the deregulation of ACD disrupts the homeostasis of the stem cell pool and promotes tumour growth. However, this mechanism is unclear. Here, we show a reduction of ACD in spheroid-derived colorectal cancer stem cells (CRCSCs) compared with differentiated cancer cells. The epithelial-mesenchymal transition (EMT) inducer Snail is responsible for the ACD-to-symmetrical cell division (SCD) switch in CRCSCs. Mechanistically, Snail induces the expression of microRNA-146a (miR-146a) through the β-catenin-TCF4 complex. miR-146a targets Numb to stabilize β-catenin, which forms a feedback circuit to maintain Wnt activity and directs SCD. Interference with the Snail-miR-146a–β-catenin loop by inhibiting the MEK or Wnt activity reduces the symmetrical division of CRCSCs and attenuates tumorigenicity. In colorectal cancer patients, the Snail(High)Numb(Low) profile is correlated with cetuximab resistance and a poorer prognosis. This study elucidates a unique mechanism of EMT-induced CRCSC expansion.
Comment in [Nat Cell Biol. 2014] PMID:24561623
Figure 1: Cell division modes used by cancer stem cells and their regulation in colorectal cancer. (a) Colorectal cancer stem cells (CRCSCs) undergo symmetric self-renewing divisions giving rise to two self-renewing daughter cells (red). The red curved arrows indicate self-renewal. (b) CRCSCs also undergo asymmetric self-sustaining divisions by localizing cell fate determinants with opposite functions (red and blue crescents) to opposite poles, thereby generating one self-renewing (red) and one differentiating (blue) daughter cell. (c) Symmetric differentiating divisions can also be induced in non-CSC colorectal cancer cells (blue); for example, by the presence of miR-34a (ref. 12). (d) Model of integrated regulation of cell division mode, tumour progression and metastasis. Left: miRNA-regulated Wnt and Notch signalling promotes symmetric self-renewing cell divisions of intestinal stem cells at the bottom of intestinal crypts. In non-neoplastic stem cells and CRCSCs from early tumour stages, Snail expression is low or absent, whereas Numb expression is high, leading to proteasomal degradation of β-catenin (β-cat) and attenuation of Wnt signalling. As a result, intestinal stem cells and early-stage CRCSCs divide asymmetrically. Right: Hwang et al.3 propose a positive feedback mechanism in late tumorigenesis, whereby the Snail-dependent action of nuclear β-catenin (β-catn) and TCF4 induces miR-146a expression and the subsequent downregulation of Numb. This relieves the Numb-mediated degradation of β-catenin and enhances Wnt signalling, thereby increasing symmetric divisions and maintaining the self-renewing CRCSC phenotype. The Snail–β-cat–miR-146a axis promotes tumour growth and metastasis, in part independently of the epithelial-to-mesenchymal transition (EMT).
Cancer Cell. 2014 Oct 13;26(4):534-48. doi: 10.1016/j.ccell.2014.09.002.
Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages.
Hsu DS1, Wang HJ1, Tai SK2, Chou CH1, Hsieh CH3, Chiu PH1, Chen NJ4, Yang MH5.
Abstract

Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation. CBP interacts with Snail and acetylates Snail at lysine 146 and lysine 187, which prevents the repressor complex formation. We further identified several Snail-activated targets, including TNF-α, which is also the upstream signal for Snail acetylation, and CCL2 and CCL5, which promote the recruitment of tumor-associated macrophages. Here, we present our results on the mechanism by which Snail induces target gene transactivation to remodel the tumor microenvironment. PMID:  25314079

Significance

The understanding of Snail as an activator is relatively limited, compared with the knowledge of Snail as a repressor. Here, we identify the mechanism that guides the activity of Snail through the acetylation of Snail. The “yin and yang” effect of Snail is, therefore, elucidated; “repressor Snail” inhibits adherent protein expression to promote the disaggregation and migration of epithelial cancer cells, whereas “activator Snail” induces mesenchymal proteins to complete EMT and cytokine expression to remodel the tumor microenvironment. The paracrine effect of cells undergoing EMT has been highlighted, explaining the pivotal role of these stem-like cancer cells in host-cancer interplay.

Figure 8. Clinical Significance of Snail Acetylation in Head and Neck Cancer Patients. (A) PLA for detecting acetylated Snail (left) and IHC for analyzing CD68+ (middle) or CD163+ (right) macrophages in head and neck cancer patients. The arrows indicate the representative PLA-positive signals. Case 1 is a representative case with increased acetylated Snail and CD68+/CD163+ macrophages. Case 2 is a representative case with low acetylated Snail and macrophage recruitments. Scale bars: for PLA photo, 20 μm; for CD68/CD163 IHC, 200 μm. (B) The box plot for showing the percentage of PLA-positive cells in CD68low versus CD68high (upper panel) and CD163low versus CD163high (lower panel) head and neck cancer samples (n = 15). The p value was shown in each panel. The box plots represent sample maximum (upper end of whisker), upper quartile (top of box), median (band in the box), lower quartile (bottom of box), and sample minimum (lower end of whisker). (C) Representative results of immunohistochemistry using the antibody against acetylated Snail lysine 187 or a macrophage marker CD163 in head and neck cancer samples. Case 1, a representative case of increased acetylated Snail in cancer cells and tumor-associated macrophages. Case 2, a representative case of low level of acetylated Snail in cancer cells and few macrophages. Scale bars, 200 μm. (D) A Kaplan-Meier analysis of the progression-free survival in 82 head and neck cancer patients. The p value is shown in the panel.

 

Acetylation of Snail in Head and neck cancer !! acetylation of snail --> transcriptinal activator!

Tumor Microenvironment in HNSCC (Cancer Cell Oct-2014) http://eln.nhri.org.tw/lims/?q=node/1836 按我

#8由 sufang 在 六, 11/01/2014 - 10:13 發表。

安康教授: From nutrient deficiency to mitochondria dysfunction

安康教授: Dr. David K. Ann, Dept Metabolic Diseases Beckman Research Institute, City of Hope, USA
 
From nutrient deficiency to mitochondria dysfunction: a translational study of targeting arginine auxotrophic cancers
  • Challenage: breast cancer treatment resistance (autophagy)
  • (a) Low glucose and hig lactate  (Warburg Effect) (b) High amino acids (autophagy) (c) High levle of energy (high proliferation)
  • Arginine metabolic pathway (ASS1: argininosuccunate syntherase 1
  • NKI947 ER+ve versu ER-ve: ASS1 (low ASS1-expressin is an independent indicator for breas cancer adn Achilles' Heel) MSA-MB231 (ASS1 is not detectable; MCF7 and MCF10A, ASS1 is high)
  • Arginine deprivation (ADI; arginine deiminase):  targeting ASS1-deficien t tumors
  • The ability of ADI-PEG20 in inhbiting MDA-MB231 cells but less to MCH7 (ADI-PEG20 inudced autophay-depedent cell death)
  • Starvation induces autophay (self eating) 餓=食+我 Mol Cell
  • Good association between ASS1 and NUDFA9 (complex I) and SDHA (mitochondria complex II)
  • ADI-PEG20 impairs mitochondrial OXPHOS function
  • Glucose --> --> --> pyruvate (a) glucose oxidation (b) ---  用海馬(sea-horse) 測量用氧量 (basal and maxium OXPHOS)
  • oligomycin FCCP rotenone (2014 Science Signaling)
  • Tumor selective suppreson of ASS1 ernders cancer cells addicted to externa largiine and vulnerable to argine
  • PNAS and Austin 2014
  • Arginine starviation mitochondrial dysfuncutn ROS excessive autophagy --> point of no return (http://www.ncbi.nlm.nih.gov/pubmed/25122679)
#9由 sufang 在 六, 11/01/2014 - 10:08 發表。

馮新華教授: How cancer cells escape from TGF-b control?

3. 馮新華教授 (Xin-Hua Feng, Life Sciences Institute, Zhejiang University, PRC)

  • CDK inhibitors p15 and p16
  • TGFb signaling and human diseases (Cancers/Fibrosis.)
  • TGFb is a key anti-growth factor
  • cell cycle arrest, cell differentiation, embryogenesis, organgenesis, immune regulation
  • Cacner: escape from TGFb control. Once they escape, they become resistant to it.
  • Ways to escape: mutaton TGFbR, in SMAD4 (in MH2 domain causes trasactivation domain defect) panc 55%, colon 30%), incactivation of p15 and p16
  • Cancer-derived MH1 muation (K113/159R)  lost SUMOylation and increased Ubiquitination in R100T mutatnt
  • high binding affinity of Smad4 mutants to SCFsp2 E3 ligase
  • pathways to the destructin of Smad4: SMAD -> p38/JNK -> SCF/skp2 -> proteosme
  • Muation switches Smad4 from SUMO to ubiquitin conjufatin in cancer
  • SMADs and TGFb receptors are rarely deleted in breast caner, colon caner, lymphoma
  • Bcl6 causes TGFb resistance in B-celll lymphoma cells: BCL6 inhibtis SMAD4, which is required for TGFb-mediated cell growth arrest
  • Bcl6 is a transcription corepressor for Dmad4; Bcl6 disrupts Smad4-p300 interaction
  • ALK (case II).  NPM-ALK attenuates TGF-b-induced transcriptional responses
  • siALK enhances TGF-b-induced trnacriptinal respinses; NPM-ALK imparis SMad4's DNA binidng -> loss of DNA binsing --? loss of TGFb growth inhibition -> TGFb resistance; tumorigensis
  • NPM-ALK attenuates Smad tumor suppressor activity (MDA-MB 468 is Smad4 null)
  • Working model for ALK actions
  • Summary: TGFb signaling is a tumor suppressor pathway ; TGFb induces CKI eg p15 and p21, p57 to arrest cells in G1; TGFb escape is trought (A) mutations of TGFb receptor , SMAD (B) trought Bcl6/ ALK
#10由 sufang 在 六, 11/01/2014 - 10:01 發表。

陳慶士所長: Fighting an organized crime network in pancreatic cancer

陳慶士所長: Fighting an organized crime network in pancreatic cancer: tumor and its microenvironment
  • Current targeted therapy: one dimentional
  • Pancreatic cancer, an organized crime network (Gasterenterology: 2013; 144: p1210)
  • A multi-prong strategy for pancreatic caner therapy: cancer cell, stromal cell, stella cell
  • Hypothesis: the KRAS-ILK regulatory circuitry represents a druggable target
    • Oncogenic Kras is required for both the initation and maintenance of pancreatic encer.
    • 成大 朱博正
    • ILK: cell line specific , PDK2-like, GSK3b, MCL, myosine Ptase taret subnit, cNAC, b-paviin; a scaffold protein
    • Downstream signalign markers: MAPK, ErK, W2F1, YB1, EGFR... KRAS--> E2F --> ILK
    • ILK regulates KRAS expression through hnRNAP A1-mediated disruption of G-quadruplex in KRAS promoter
    • ILK: a signaling node between oncogenic KRA and TME.
    • (a) Maintenance of KRAS expression (b) Promotrion of aggressive phenotype
    • EFfect of dox-induced ILK KO on EMT (enforced expresson of CA-ILK abolises teh supprssive ffect of KRA..)
    • Stromal ILK is overxpressed in pancreatic cancer


#1由 sufang 在 六, 11/01/2014 - 09:57 發表。

Dr. Alex Chang 張元吉教授

Dr. Alex Chang 張元吉教授 (Johns Hopkins Singapore International Medical Centre, Singapore) Combination targeted therapy in advanced lung cancer

  • Combined targeted therapies in advaned lung cancer/Transformation in treatment (biomarker for treatment)/
  • ErbB receptor signaling Cancer Dis 2014; 4: 991-994
Mechanisms of EGFR inhibitor resistance and therapeutic strategies.
  • Vertical blockade and horizonal blockade/Third generation of EGFR TKI, against T790M
  • Successful examples of combination of targeted agens (Melanoma dabrafenib+trametinib; adenocarconima of lung. EGFR muation positive Cetuximib + Afatinib =BIBW-2992)
  • Src in NSCLC, clinically dasatininb had little activity in unselected, refractory NSCLC.
  • Combinaiton of satstinib in combinaiton with dasatinib
  • FAK, a downstream molecule of Src, shows effective inhibition of combination of targetd agent (sasatinib + afatinib) the combinaitn inhited EGFR, HER2, SRCm FAK, AKT
  • Dasatinib combined with afatinib in PC9 (Japanese group)
  • Rationale for combining IGF-IR and ALK inhbitors (ALK fuson rotien, similar to IGF-IR binds to the adaptor insulin receptor substrate IRS-1 and IRS1 knock down enhances the antitumor effets of ALK inhibiton) (Seto Lancet Oncol: 2014 (http://www.ncbi.nlm.nih.gov/pubmed/25175099)
 
張貼者： 於

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