Pharm - Heme - Cancer Novel Targets

Front 1

Length of time to get a drug out

Back 1

About 15 years.

Front 2

Phase 1

Back 2

Point is to find toxic level.

Also finds dosage.

20-40 people

Front 3

Phase 2

Back 3

Determine dose and early efficacy in 40-100 people

Front 4

Phase 3

Back 4

Random study in 500 or more people. Placebo often used.

Purpose is to assess activity in a specific clinical setting and get FDA approval.

This often needs to be done twice.

Front 5

Phase 4

Back 5

Post-marketing study. Many companies don't do these.

Front 6

Oncogene examples

Back 6

Ras (15% of CA), chromosomal translocations, gene amplification (i.e. EGFR or her-2/neu)

These are pretty easily targeted.

Front 7

DNA amplification - specific example where it is used

Back 7

To decide if pts should get herceptin tx.

Front 8

Tumor suppressor gene examples

Back 8

p53 (75% of CA), BRCA

Chrom/DNA deletion (e.g. p53 retinoblastoma gene, DCC)

Gene silencing (e.g. p15 or p16) - this is epigenetic.

These are difficult to target.

Front 9

Things to target

Back 9

Oncogenes, TSGs or the environment (e.g. stroma, vasculature)

Front 10

Benefits of combo therapy

Back 10

Overcome resistance and reduce SE of indiv drugs.

Front 11

Resistance often occurs due to...

Back 11

Mutations of the target.

Front 12

Retinoids

Back 12

ACTIVATE NUCLEAR TXPN FACTORS


Derived from vit A

Vision, fertility.

Effects in development, neoplasia, normal cells.

Front 13

ATRA

Back 13

Used in APL.
For the RAR receptor.

Front 14

RAR and RXR receptor

Back 14

Subtypes are alpha, beta, gamma. Binds ligands and DNA (so does RXR)

Front 15

Bexarotone

Back 15

For the RXR receptor.

Indicated in cutaneous T cell lymphoma.

Front 16

Mechanism of retinoic acid.

Back 16

Switch is normally off. When endogenous ligand is added, interacts with RAR and HATs modify DNA to open it up and allow for RXR/RAR to txp DNA

In cancer, normal amounts of retinoic acid don't allow for the inhibitor elements to be displaced.

Front 17

Oral leukoplakia

Back 17

RAR-beta receptor is messed up and retinoic acid helps.

Front 18

APL

Back 18

t(15;17) and PML/RARalpha

This causes a rearrangement of the RA receptor.

ATRA in combo with chemo causes remissions through differentiation of this leukemia.

Front 19

APL - 3 types

Back 19

Short translocation product
Long translocation product
No translocation product (does not respond to ATRA)

So you must tailor the therapy to the genetic profile of the cancer.

Front 20

SE of ATRA

Back 20

Leukostasis in the lung causing early death. (so you want to combine it with chemo)

Front 21

Mechanisms of resistance in APL

Back 21

most common - Mutation of RA receptor binding domain (can't bind ATRA)

ATRA normally induces it's own catabolism over time via p450

RA normally induces expression of a cytosolic receptor over time so more of it is sequestered out of nucleus.

Originally there was no mutation in RA receptor - but the mutation was a PLZF/RARalpha.

Front 22

Her-2/Neu

Back 22

Overexpressed in some of the poor prognosis breast CAs

Front 23

Herceptin

Back 23

Anti-her-2/neu receptor antibody. Works on surface vs nucleus (ATRA)

Good in advanced estrogen resistant breast CA

Combine it with chemo.

IT CHANGES THE BIOLOGY FROM A POOR PROGNOSIS TO A GOOD PROGNOSIS!!! (not a cure)

Front 24

EGFR

Back 24

Ligand is EGF.
A tyrosine kinase.
Leads to growth.

Mutation is often amplification of the signal due to autophosphorylation.

Front 25

Drugs to stop overexpression of EGFR

Back 25

Tyrosine kinase inhibitor or antibody against the receptor.

They change the genotype.

In responding patients, they often acquire a mutation that allows the drug to work even better.

Front 26

Types of pt that often responds to tyrosine kinase inhibitor

Back 26

Woman, asian, never smoked, cronchioalveolar carcinoma, activating EGFR mutations.

Front 27

Gleevec (imatinib)

Back 27

CML

Activity in chronic and blast phases (a little less activity in blast phase)

Complete remission can occur.

Works by preventing phosphrylation - binds to the active site of BCR-ABL kinase where ATP would normally bind and subsequently transfer a phosphate to tyrosine kinase receptor.

Resistance occurs when gleevec can no longer bind to BCR-ABL kinase.

Front 28

Drug to overcome Gleevec resistance

Back 28

Dasatinib. Also binds in BCR-ABL pocket.

Front 29

Other indictation of Gleevec

Back 29

Also targets Kit receptor tyrosine kinase (often overactivated in gastrointestinal stromal tumors).

Front 30

Sorafenib

Back 30

Very promising - targets Rad, VEGF, PDGF.

Good for renal and hepatocellular cancers.

Great against metastatic melanoma when B-raf mutations occur.

Front 31

Angiogenic factors

Back 31

bFGF, EGF, PDGF

Front 32

Anti-angiogenic factors

Back 32

Anti-VEGF, endostatin, angiostatin

Front 33

Why anti-angiogenic factors are promising

Back 33

Crosses histogies and resistance is infrequent (normal vascular cells are targeted.

Activity doesn't depend on the tumor cell targeted

Chronic therapy could prevent vascularization of tumors.

Front 34

What kind of CA not indicated for certain anti-angiogenic drugs?

Back 34

Squamous cell CA because these drugs can cause bleeding complications resulting to life-threatening hemoptysis.

Front 35

Vessels supplying tumors

Back 35

Very leaky. So one strategy is to normalize these vessels for a little and then deliver anti-neoplastic drugs through these good vessels.

Front 36

Two very new novel therapies in oncology

Back 36

Targeting specific RNAs (small interfering RNA and anti-sense RNA) and microRNAs.

Small molecule inhibitors of cancer stem cells.

Front 37

Cancer stem cells.

Back 37

They have limited proliferative potential and self-renewal just like normal stem cells, but they form malignant progeny.

These are a small subset of the cancer but are causing all the problems. They are also v. resistant to chemo.

Front 38

Hedghehog inhibition

Back 38

Hedgehog is normally a key growth factor regulatory pathway in development and in cancer.

Inhibiting it shows great response in medulloblastoma and invasive basal cell cancers.

Its negative regulator is Patched, and it is often mutated due to hedgehog.