경희대학교 의과대학·의학전문대학원

전체 글

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Clinical Application of Cancer Cell Biology

1. Cell cycle check points

2. Cell senescence

3. Signal transduction pathways

4. Epigenetic influences

5. Apoptosis

6. Tumor angiogenesis

7. Cancer stem cell

Characteristic Features of Cancer

• Characteristics

– Unregulated cell growth

– Tissue invasion/metastasis

• Cancer is genetic disease

– Mutations in several different genes.

• Cell proliferation, survival • DNA repair

• motility, invasion • angiogenesis

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Phenotypic Characteristics of Malignant Cells (I)

• Deregulated cell proliferation

– Release of supression(Rb, p53) – Oncogene activation(Ras, Myc)

– Aberrant cell cycle control( loss of normal checkpoint response)

• Failure to differentiate

– Arrest at a stage prior to terminal differentiation • In leukemia due to chromosomal translocation

• Loss of normal apoptosis pathways

– Inactivation of p53, increases in Bcl-2 family members

• Genetic instability

– Microsatellite instability(MIN), chromosomal instability(CIN) – Defect in DNA repair pathways

• BRCA1/2, p53, mismatch repair gene(MMR)

• Loss of replicative senescence

– Normal cell stop dividing after 25-50 doublings – Arrest is mediated by the Rb and p53 pathways

Phenotypic Characteristics of Malignant Cells (II)

• Increased angiogenesis

– Increased gene expression of proangiogenic factors

• VEGF, FGF, IL-8

• Invasion

– Loss of cell-cell contacts (gap junctions, cadherens)

– Increased production of matrix metalloproteinases (MMPs) – Form of epithelial to mesenchymal transition(EMT)

• Metastasis

– Spread of tumor cells to lymph nodes or distant site

• Evasion of the immune system

– Downregulation of MHC class I & II molecules – Induction of T cell tolerance

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Genetic Events in Colon Carcinogenesis

normal early adenoma

Intermed adenoma

late

adenoma carcinoma metastasis Microsatellite Instability (MIN)/Chromosomal Instability (CIN)

APC inactivation or -catenin activation K-RAS or BRAF activation SMAD4 or TGF II inactivation P53 inactivation Other alteration

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Therapeutic application of pRB/p53

• pRB

– Loss of function

• Cancer cells enter a mitotic cycle

– Therapeutic application

• Selective CDK inhibitor

– Flavopiridol

– Phase II clinical trial in CLL

• p53

– Most common genetic alteration(>50%)

• Li-Fraumani familial cancer syndorme: germline mutation

– Compromise cell cycle arrest  chromosome instability

– Therapeutic application

• Oncolytic viruses(adenovirus)

– Phase II clinical trial in H&N cancer

Gompertzian Tumor Growth

Chemosensitive period: small tumor burden maximal growth fraction

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Normal Somatic Cells

Normal Germ Cells or Cancer Cells

telomerase telomerase

Senescence

immortal

Senescence

• Reverse transcriptase activity of telomerase is a prime target

• Telomerase vaccines

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Therapeutic targeting of signal transduction pathways in cancer cells

STI571

“Imatinib”

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Pathways activated by Bcr-Abl

Efficacy of Imatinib in CML

Chronic phase (n=532) Accelerated phase (n=235) Blast phase (n=260) Hematologic 95% 34% 7% cytogenetic 41% 17% 7%

Imatinib vs Interferon+cytarbine, NEJM 348:11, 2003

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Imatinib

in c-kit

positive

GIST

After 8 months initial NEJM 347:472, 2002

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P<0.001

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erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 HRG (NRG1) Tyrosine kinase domain Ligand binding domain Transmembrane

Mendelsohn and Baselga. Oncogene. 2000;19:6550. Olayioye et al. EMBO J. 2000;19:3159.

Prigent and Lemoine. Prog Growth Factor Res. 1992;4:1. Harari and Yarden. Oncogene. 2000;19:6102. Earp et al. Breast Cancer Res Treat. 1995;35:115.

The EGFR/HER Family

Targets HER2 protein

High affinity (K

d

= 0.1

nM) and specificity

95% human, 5% murine

Decreases potential

for immunogenicity

Increases potential for

recruiting immune effector

mechanisms

HER2 epitopes recognized by hypervariable murine

antibody fragment

Human IgG-1

Trastuzumab(Herceptin

®

)

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Months 0.2 0 0.4 0.6 0.8 1.0 HER2-FISH(+) Months 0.2 0 0.4 0.6 0.8 1.0 Trast. + CT (n = 176) CT (n = 169) Probability of surv iv a l RR = 0.71 p = 0.007 0 10 20 30 40 50 20.0 mo 26.2 mo HER2-FISH(–) RR = 1.11 p = NS 0 10 20 30 40 50 19.8 mo 24.0 mo Trast. + CT (n = 50) CT (n = 56)

Trastuzumab Combination Pivotal Trial:

Overall Survival

Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.

Trastuzumab after Adjuvant chemothx

in HER2-Positive Breast Cancer

(HERA trial)

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Lancet 2010;376:687

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Downstream of RTKs: Ras & PI3K

• Ras

– Mutation in 20% of human cancer • Pancreas, colon, lung, AML

– Therapeutic application • Farnesyl-transferase inhibitor

– Some activity in AML

• BRAF kinase inhibitor: vemurafenib

• PI3K

– Serine/threonine kinases Akt & PDK1 – Activated in 30-40% of human cancer

• Breast, colon, brain, gastric, ovary

– Therapeutic application

• mTOR inhibitor – temsirolimus

– renal cell carcinoma

Normal BRAF is activated by interaction with KRAS. In melanoma, BRAF V600 mutant proteins have high unregulated kinase activity that impels cell proliferation and tumor growth.

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NEJM 364;26, 2011

PR: 48%

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(Results)

Patients who received temsirolimus alone had longer

overall survival (hazard ratio for death, 0.73; 95%

confidence interval [CI], 0.58 to 0.92; P = 0.008) and

progression-free survival (P<0.001) than did patients who received interferon alone.

Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P = 0.70).

N Engl J Med 2007;356:2271-81

Tumor angiogenesis

• Angiogenic switch

– Ability of tumor to promote formation of new capillaries

– Stimuli for angiogenesis

• Hypoxia, inflammation, genetic lesions

– Steps of angiogenesis

• Stimulation of endothelial cells(ECs) by growth factor • Degradation of ECM by proteases

• Proliferation of ECs and migration into tumor • Eventual formation of new capillary tubes

• Trophic angiogenic molecules

– VEGF

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Angiogenesis is involved throughout

tumor formation, growth and metastasis

Adapted from Poon, et al. JCO 2001

Stages at which angiogenesis plays a role in tumor progression

Premalignant stage Malignant tumor Tumor growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumor) (Angiogenic switch) (Vascularized tumor) (Tumor cell intravasation) (Seeding in distant organs) (Secondary angiogenesis)

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Knowledge of the molecular events governing tumor angiogenesis has led to a number of therapeutic strategies to block tumor blood vessel formation

Antiangiogenic therapy

• Bevacizumab

– Colon, lung, breast, renal cell cancer – Combination with chemotherapy

• Single agent activity in RCC

– Mechanism

• Normalization of blood flow in tumors  enhance the delivery of cytotoxic

agents

• Inhibition of growth of new tumor vessels  nutritional deprivation 

tumor cell death – Side effect

• Hypertension, arterial thromboembolic events, hemorrage, bowel

perforation

• Sunitinib

– Multitarget: VEGFR, PDGFR, c-kit receptor

– RCC, GIST • Sorafenib

– Multitarget: VEGFR, PDGFR, Raf kinase inhibitor

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P<0.001

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Molecular Pathways & Targeted Therapies in RCC

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Epigenetic Changes in Cancer

Alteration of chromatin structure: • Methylation of CpG islands

• Modification of histones by acetylation

Epigenetic change

• Epigenetically silenced

– Pancreatic cancer, multiple myeloma

• Methylation of p16ink4a promotor  pRb nonfunctional

– Renal(VHL), breast(BRCA1), colon(STK11)

• Acute promyelocytic leukemia

– PML-RAR fusion protein

• Bind to promotor and recruits HDAC  inhibit gene expression – ATRA

• Release of HDAC activity

• HDAC inhibitor

– Vorinostat: cutaneous T cell lymphoma

• Reverse the hypermethylation of CpG island

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Apoptosis

• Extrinsic pathway

– TNF receptor family(

Fas, DR4, DR5), Fas ligand, TRAIL

– Caspase-8

• Intrinsic pathway

– Death inducing signals

– SMAC(second mitochondrial activator of caspases)

• Therapeutic application

– Targeting of antiapoptotic Bcl-2 family member

– Targeting DR4 & 5

• Recombinant human TRAIL

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Cancer Stem Cell

• Unlimited self renewal • Proliferate extensively • Less vulerable to

chemotherapy or radiation

– Slow cell cycle

– High expression of Bcl-2 families and MDR family

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Senarios Involving Cancer Stem Cells

Bench to bedside: Translational research

Application of basic

scientific discoveries

Generation of scientific questions

based on clinical observations

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Advances in Cancer Therapy

Surgery/Radiation Local Control

Combination chemotherapy Improved response rates

Adjuvant chemotherapy Induces cures

Dose intensity Augments adjuvant Rx

Molecularly directed Rx’s: Increase specificity

Molecular guided therapies: Optimized treatments

“Personalized Treatment based on Molecular Profiles”

Multigene Assay to Predict Recurrence of

Tamoxifen-Treated, Node-Negative Breast Cacner

Soonmyung Paik, MD., NSABP

N Engl J Med 2004;351:2817

16 cancer related genes(selected from 250 candidate genes) 5 reference genes

NSABP trial B-20, B-14(2892 patients) Paraffin block, RT-PCR(Oncotype DX assay)

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Prediction of Survival in Diffuse Large-B-Cell Lymphoma Based on

the Expression of Six Genes

Izidore S. Lossos, Stanford University

N Engl J Med 2004;350:1828

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The Use of Moleular Profiling to Predict Survival after Chemotherapy for Diffuse

Large B Cell Lymphoma

N Engl J Med 2002;346:1937

“Lymphochip”(12,196 clones)

-genes for lymphoid cells

-Genes for cancer/immune function

Personalized Treatment

Tailored therapy

• Treat the populations

Treat the individual!

• Treatment rationales come from

– the basic biology of each patient (variation)

• Needs the clinical trials for supporting the individualized

therapy

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