cancer and cell death

cancer and cell death

problem

there are 200+ histologically different cancers which are based off exactly which genes are mutated

solution

figure out the molecular basis and create treatments based on those issues

problem 2

there is an increased rate of younger people getting cancer due to increased rates of cellular aging

problem 3

cancer cells have 5 “driver mutations” that are directly involved in the cancer

solution 3

target the 5 driver mutations directly

tatiana schlossberg - Jfk granddaughter

was diagnosed with acute myeloid leukemia — mutation due to INVERSION 3

• went through with a bone marrow transplant, chemotherapy, and CAR-T cell therapy but was unable to get cured

dr yin cao — washinghton school of medicin in st louis

looked at 148,724 people ages 37-54, uk biobank

• looks at albumin, creatine, glucose.. in the blood at found that those who were the oldest baSed on these biomarkers hae twice the risk of early onset lung cancer, 60% increase gi tumors, and 80% higher risk.

zebra fish

the model organism to study mutations that cause melanoma

zebra fish qualities

• transparent embryos

• genetic similarity to humans

• rapid development

general progression of cancer

1. initiation

2. cancer. progresses — mutation and genome destabilization, dysregulation of growth control pathways

3. evasion of cancer cell elimination — blocks apoptosis, t cells block killing

4. tumor groth and dispersion

normal cells will

commit anoikis in a semi-solid medium

secrete low amounts of proteases

secretes lots of ecm

abide by hayflick limit

normal cells are

the typical karyotype

larger than cancer cell

mortal

normal cells have

normal miRNA set

more cytoplasm then nucleus

an organized cytosketon

a single layer growth in vitro due to contact inhibition

fewer genetic defects

normal cell membrne permeability

no angiogenesis factors released

normal apoptosis

normal rtk fucnction

shorter telomeres

normal cells do not

cause cancer in sids mice

cancer cells will

grow in semi-solid medium

release angiogenesis fators to create blood vessels for nutrients

hinder rtk function

cancer cells are

sometimes smaller than normal cells

immortal

cancer cells have

missing or extra chromosomes (aneuploid)

abnormal miRNA sets

less cytoplasm than nucleus

little ecm ssecreted so it can move around better

no vitro inhibition meaning it forms a multilayer in vitro

lots of genetic defects

wardburg effect sometimes

membranes that are 10X more permeable to allow more things to flow through

cancer cells will

secrete alot of proteases to promote movement

perform continuous repitition to prevent organized cytoskeleton

cause tumors in sids mice

rous sarcoma virus —

discovered by rous in 1911 which consists of a retrovirus causing cancer

sv40 virus

uses dna

has a large t shape antigen

afftct the P53 and RB

ebv

mono

Gardasil

first drug to prevent 90% of hpv caused cancer

radiation

there are high childhood leukemia rates among atomic bomb survivors

uv light

affects thymine-thymine dimers

v-src

the oncogen that caues cancer

c-src

proto oncogene

chemical mutagens

tobacco smoke which has 60+ mutagens

defective cyclins

cyclin d1 being over amplified in 50& of breast cancers

defective tumor suppressor genes

brca and p53

defective caretaker genes/ corrector enzymes

can cause xeroderma pigmentosum

defects in

apoptosis

defects in gf pathways

rtk mutations

defective telomeres

they dont shorten

cancer stem cells

1. all cancers have csc’s

2. are very few in number- make up less than 1% of the tumor

3. can self renew and differentiate

4. are the main cause of recurrence and metastasis

5. are very resitant to chemo and radiation

cd133

marker enzyme for cscs

imatinib and hdaci

can be used together to treat cscs by inhibitiing the fused protein from harming the cell

burkitts lymphoma is caused by

chromosomal translocation

bar-abl protein kinase

genes that are fused together and causes fuwed proteins that do not function as they should

dna amplifiction

• the over expression of or the overproducion of mutated/defective transcritption factors

can lead to rtk overproduction

robert weinburg

discovered the first tumor suppressor gene RB

robert weinburg took

1. DNA from human bladder cancer and put it in 3t3 cell lines

• the 3t3 cells started to form a multilayer

the insertion of human baldder cells in the 3t3 cells showed that

cancer is not species specific because 3t3 is a mouse cell line and the cancer came from humans

ron weinburg and the Ha-Ras oncogne placed in the 3t3 cells line and tumor formed

1. put ha-ras in rat embryo fibroblast and the tumor did not form

2. placed ha-rd rat embryo fibroblast and placed it on soft agar and a tumor formed

cancer is age dependent because

the accumulation of mutations in cells increase over time

multi hit model — mice with myc gene mutation

no cancer

mice with rat mutations

little bit of cancer

mice with myc and ras

high level of cancer

colon cancer

a huge killer but it is very slow and treatable

colon cancer progression step 1

starts as a polyp— generally benign and appears in 55% of colonoscopies

• can be removed and thus prevented from becoming malignant

after polyp developemnt

years can pass and it becomes malignant and progresses into cancer

• occult blood tests are not enough

tumors originate from

one cell due to female XX chromosome inactivation

tumors appear as

red

ocogeneic mutations

the gain of function

tumor suppressor

the loss of function

sffv — spleen focus forming virus

can cause erythroleukemia which is the cancer of rocs

neu oncoprotein — rtk mutation

protein coded by oncogene

binds the her2 and converts valine into glutamin and disrupts the rtk

sffv — spleen focus forming virus steps

normally epo will bind to the repo rtk to form regulated rbc production

sffv — spleen focus forming virus will use

glycoprotein 55 to do epo functions without regulation

rb

first tumor suppressor gene discovered

• causes retinoblastoma mainly in children

can be inherited

rb+ mutating into rb-

can be non-inherited (sporadic)

both rb+’s mutating into rb-.

li-fraumeni syndrome is caused by a

p53 mutation

• 25x more likely to dvelop cancer later in life

brca-1

a defect in this increases the likelihod of feveloping breast cancer by 60%

carcinogens

directly causes cancer

indirect carciogens

metabolized by liver and cytochrome p450 into a direct carcinogen

• aflatoxin — peanut fungus — mutates p53

radiation goal

to damage dna to force the cell to get regulated by mitotic checkpoints and undergo apoptosis

brachytherapy

injecting radioactive isotopes near the tumor

cyberknife

• external beam radiationn therapy

• a highly foccused beam of radiation which is used mainly for brain cancer

surgical ablation (removal/resection)

uses a da Vinci robotic system for prostate cancer

galleri tests

can test blood samples for cancer in older adults

monitoring cfdna ( circulating tumor dna)

will be helpful in guiding therapy for melanoma

scn and psn systems

was developed by a ccpsi biotech to use cryablation to treat multiple types of cancer

taxol -chemo drugs

a natural product that targets microtubules and triggers the m checkpoint

taxotere

a semi synthetic molecule that triggers the m checkpoint

5-fluorouracil

targets thymine and uracil by adding a f on them which forcefully triggers checkpoints

tamoxifen

a competitive antagonist of estrogen receptors

• 8/10 breast cancers require estrogen or progesterone for tumor growth

biologics history

Herceptin was first mAb produced

Kadcyla first conjugated Ab produced after mAbs

Used conjugated Abs to produce bispecific and trispecific Abs

herceptin

prevents her2 dimerization and inhibits function

her2 is overproduced in many breast cancers

• her2 receptor will normally triger tumor growth and division when not inhibited

kadcyla

herceptin with dm1 toxin to apoptose cells

prolems with herceptin nd kadcyla

They will target and bind to all Her2 receptors, even those on healthy cells

solution to herceptin and kadcyla

It was found there is one amino acid difference healthy her2 cells and her2 cancer cells

• mAb was used to target the cancer her2 receptors

helix bipharmas mab l-dosa47

has uresa in it which kills cancer cells by increasing the extracellular ph so that cell undergoes apoptosis

Avastin

an anti vascular endothelial growth factor that blocks the growth of blood vessels so that angiogenesis does not occur

immunotherapy

directs T cells to fight cancer by stimulating the immune system or introducing immune system components to increase immune function

provenge

Activates immune cells to multiply, target prostate cancer cells — extremely expensive (100k for 4 months of treatment )

immunotherapy pioneers — given a 2018 nobel prize

dr honjo and dr allison

car-t

• T cells are collected from cancer patient

• then fused with viruses so that the virus can transfect the T cells with genes

• wants to produce proteins that willl target the cancer cells

• T cells are then placed back into the patient

car-t challenges

Can cause secondary malignancies like positive CAR lymphoma

• Tumor cells can inhibit T cell function

• Hard to only target cancer cells and not healthy cells

• increase in Toxicity can lead to cell death

• Only works for non solid tumor but 90% of adult tumors are solid

apoptosis

Single cell death

Programmed

Membrane blebbing

has Little inflammatory response

Phagocytosis

Neat

Needs ATP

DNA compacted

Ladder

necrosis

Grouped cell death

Membrane lysed

Significant inflammatory response

Inflammatory cells kill them

Messy

No ATP needed

Streak

levi montalcini

noticed apoptosis cells in chick embryo brain

kerr

Liver ligation experiment

• has a portal vein that feeds liver with blood restricted and noticed that cells underwent necrosis and “shrinking necrosis” (apoptosis)

horvitz

discovered apoptotic genes in c.elegans (roundworm)

chronic lymphocytic leukemia (cll)

can be cured by cell therapy using car t cells

car t cells are effective in

treating solid brain tumors

• cancer is called dipg or diffuse intrinsic pontine glioma

Keytruda

a mAb that blocks the PD-L1 (dont kill me signal) on T cells

• PD-1 binds to PD-L1 on cells to prevent immune system rom killing them

magnetically guided microbots delivering drugs with pinpoint accuracy

• through the vasculature — tested in pigs

• magnetism delivers the robot and controlled heating can deliver the drug at the target by dissolving the robot

can decrase the side effrects with systemically delivered chemotherapy