Cancer Molecular Therapy

Question 1

Tools for dealing with cancer

Answer 1

1. Surgery
2. Radiation
   3.

Question 2

Surgery

Answer 2

use when well delineated tumor in accessible site where loss of that pariticular tissue isn’t an issue

Question 3

Radiation

Answer 3

deliver ionized radiation to site of tumor; get radiation to focus on 1 spot to decrease damage to surrounding tissues

Question 4

Chemotherapy

Answer 4

• mainstay of cancer therapy;
• uses v toxic drug kill tumor but have to balance this with keeping host alive
• toxicity aimed at things that proliferate rapidly

Question 5

toxicity aimed at rapidly dividing things

Answer 5

1. Hair follicles -> hair loss
2. Renal toxicity
3. Neuro toxicity
4. Cardio toxicity
5. Hematopoetic system (blood cells) this = v susceptible to toxicity

Question 6

Conventional chemotherpay

Answer 6

cell cycle specific drugs take advantage of the fact that most tumors have high proliferative index so spend most time in DNA replication phase which is S phase so use this as target for therapeutic intervention ;
- cells lining gut and in hemoatopoeit system also v suseptible to this

Question 7

restriction point

Answer 7

in g1 in normal cells will allow cell to pass restriction point and go through cell cycle if given growth factor or other permissive signal (cell makes decision at this point whether to arrest or to go through cycle)
- in transfomred cells signaling regulating point not fxing properly so cell doesn’t respond to normal growth controls and keeps cycling/ growing even in absence of appropriate regulatory signals

Question 8

G1

Answer 8

preDNA synthetic phase

- G1 progression occurs in response to growth factor originating MAPK signaling at restriction point

Question 9

S

Answer 9

DNA replication

Question 10

G2

Answer 10

cell getting ready for cytokeneis

Question 11

M

Answer 11

mitosis

Question 12

cell cycle specific agenst

Answer 12

• usually attacks S phase of cell cycle which we need knowledge of tumor kinetics to do
• Exploits distributive doses b/c knock out S phase cells then take drug away then G1 cells will become S phase then retreat with drug and kill those ect.

Question 13

Cell cycle phase specific agenst

Answer 13

• Methotrexate
• Hydroxyurea
• Ara-C

Question 14

Methotrexate

Answer 14

Inhibits DHFR (dihydrophobic reductase) which is necessary for DNA synth -> cell death b/c no DNA synth
- problem w/ this is use this for prolonged time -> select for tumor cells that amplify DHFR to get around this

Question 15

Hydroxyurea

Answer 15

targets ribonucleotide reductase (inhibits it) which is necessary to make deoxyribonucleotide) which will kill S phase cells bc most dependent on ribonucleotide reductase; cells in G1 pile up so release HU let the cells progress to S then readminister HU to kill them off (use knowledge of cell cycle to maximally target proliferatively active cells)

Question 16

Ara-C aka cytosine arabinoside

Answer 16

targets DNA replication

• “Fraudulent nucleotide”
• this is nucleotide but hasn’t been fixed when incorporated into DNA one strand will go bad and daughter that gets Ara-C incorporated strand will die
• b/c -> mutation can end up with cancer 20-40 yrs later from this treatment

Question 17

Non-specific agents

Answer 17

Agents are toxic without regard to cell cycle; attack cells throughout cell cycle typically with faster metabolisms which typically makes tumor cells more susceptible to them; these drugs are v toxic

Question 18

What types tumors easier to deal with

Answer 18

faster proliferating b/c easier to target; highly metastatic with slow growth v hard to target with these drugs

Question 19

non-specific agents drug types

Answer 19

1. Anthracyclines

2. Cis-platinum

Question 20

anthracycline

Answer 20

ex. Daunomycin

- Binds to DNA and causes widespread DNA damage

Question 21

Cis-platinum

Answer 21

crosslinks DNA and in turn compromises all fx of DNA

Question 22

Hormone sensitive tumors

Answer 22

Depend on hormone to grow
ex. ER positive breast cancer depends on estrogen, use antiestrogens to treat therapeutically such as Tamoxifen (ER agonist)

Question 23

Newer experimental therapeutic modalities

Answer 23

1. signaling and small molecules
2. differentiation and induction therapy
3. siRNA, microRNA
4. Bone marrow transplantaiton
5. Gene array analysis to monitor response

Question 24

Growth factor receptor pathway

Answer 24

Growth factor receptor -> grb2/SOS adaptors -> ras ->raf->MEK->MAPK->transcription factors ->cyclins/cdki/cdk->Rb->E2F->restriction point transit and S phase

** No DNA synth until Rb releases E2F which happens when Rb is inactivated via phosphorylation**

Question 25

Signaling and small molecules Gleevec

Answer 25

• try to use small molecules to target diff processes in terms cell growth and viability
• Gleevec is an ex. it targets bcr/abl kinase which is result of translocation (9,22) chormosome seminal to Chronic myeloid leukemia
• also targets other kinases such as c-kit

Question 26

Differentiation induction

Answer 26

method is to convert tumor cells (proliferatively active and differentiively immature) to near normal cell (quiescent and differentitiavely mature)
- doesn’t bear toxicity like others b/cnot trying to kill tumor

Question 27

Retionic acid

Answer 27

ex. of differntation induction
- retionoic acid guides embryo development; it has been successfully used to treat APL (acutepolycytic leukemia) which arises b/c of t(15,17) (translocation) -> PML-RARalpha this is targeted by retionic acid to overcome ineffectiveness to get tumor to differentiate

Question 28

1,25-dihydroxy vitamin D3

Answer 28

this is necessary metabolite that they have tried to use for differentiation induction but problem is that D3 mobilizes calcium and haven’t been able to deal with hyper calcification issues yet

Question 29

Antibody drug therapy

Answer 29

use monoclonal antibody to specifically target tumor

• conjugate toxic molecule to use ab to deliver it
• or use monoclonal antibody to target molecule on which tumor growth depends (molecular like receptor receptor expression specific to tumor have antibody target receptor and deprive tumor of growth receptor signaling)

Question 30

Herceptin

Answer 30

ex. of using conjugated rich ab to target tumor cell
- Herceptin- binds epidermal growth factor receptor 2 (Her2/ErbB2) and is used along with other drugs to treat breast cancer

Question 31

CHOP/ RCHOP

Answer 31

use combination of drugs to mitigate toxicity of any single drug
These two are used for diffuse Large B-cell lymphoma
RCHOP adds additional drug (cell surface antigen)

Question 32

Bone marrow transplatnation

Answer 32

If use use enough toxic drugs will kill tumor but also will kill host and the most susceptible host cells are hematopoietic cells; treat agressively with cytotoxic replacement of drugs that errdicate tumor and will also eradicate hematopoeitc system so go back and repopulate hematopoeitc system by putting in bone marrow; used to treat variety of hematological neoplasia as well as solid tumors (ex lymphoma)

Question 33

bone marrow transplantation types

Answer 33

autologous

heterologous

Question 34

autologous

Answer 34

your own cells; get patient healthy enough to harvest bone marrow and then deplete marrow of tumor cells with antibodies and keep healthy marrow cells; treat patient aggressively and put healthy marrow back
this is preferable b/c eliminates graph host dx

Question 35

heterologous transplant

Answer 35

Marrow comes from someone else that is a match biggest problem is graft vs host dx

Question 36

Gene expression arrays

Answer 36

• still experimental
• look at gene expression profile in hope of getting profile that characterizes tumor to know what drug sensitivity profilfe is
• also means of monitoring tumor and host response to drug to optimize drug delivery and minimize drug toxicity

Question 37

Gene targeting

Answer 37

small RNA mediated ways to use cells to regulate expressoin and increase ability to target drugs

• Antisense
• siRNA
• riboswtich

Question 38

antisense

Answer 38

fragment from coding region that binds mRNA and targets dsRNA for degradation via ribonuclease H

Question 39

siRNA

Answer 39

fragment comes from non coding DNA and targets complementary mRNA recruits RISC which activated by DICER which makes small fragments out of non coding DNA which act as guides to direct RISC (degradative complex) to target message (RISC will degrade the mRNA)

Question 40

ribo-switch

Answer 40

Ribo switch is larger fragment derived from non-coding mRNA that binds mRNA recruits other proteins and gets translated

Question 41

synthetic RNAs that mimic/target miRNA

Answer 41

• small fragments non-coding RNA that have cell type specific expression target putative regulatory genes for mRNA degradation ny binding at 3’URG; controls cell proliferation and differentiators; aberrations found in tumor cells that might be exploited to control them

Question 42

advantage of drugs targeting mRNA expression

Answer 42

potentail target specificity if know mechanism of tumorigenesis occurring to know where in signaling or cell cycle regulatory pathways you can target

Question 43

Major cyclins covering G1, S, M

Answer 43

Cyclins D, E, A, and B
Cyclin/CDK complexes regulated by CDKIs (P21 and P27 prominent)
Cyclin E/cdk2 regulate restriction point by regulating Rb phosphorylation so this is big target

Question 44

Wnt frizzled pathways

Answer 44

pathway often aberrantly activated in tumors; diverges from other tyrosine kinase pathway, have complex with B-catenin which comes from PM and is sent to nucleus by this pathway; wnt ligand for frizzled receptor (7 pass receptor) when activated by wnt this is shuttled is activated and this inhibits GSK-3 which = required for B-catenin to regulate transcription
Basically can target allt of things in this big pathway

Question 45

combination therapies

Answer 45

idea is that there are different ways to combine drugs to limit toxic effects but have to know which drugs interact how to avoid deleterious effects

Question 46

targeting obvious tumor enhancing gene

Answer 46

may not have desired effect cdk2 knockout mice shouldn’t;t have been able to survive yet they did (redundant fx contributes to survival which creates an issue with targeting things)

Question 47

new trend in cancer therapy

Answer 47

use agents that can specifically as possible target tumor specific chracteristics but most common agents used are still chemotherapeutic agents