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PHAR 211 - Personalized Medicine > Meena Stuff (TTs, Genomics, P.Genomics, DDP, IT in Cancer) > Flashcards

Meena Stuff (TTs, Genomics, P.Genomics, DDP, IT in Cancer) Flashcards

1
Q

What is a drug?

A

Anything that modulates physiological processes

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2
Q

What makes a good drug?

A

Potent & Specific

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3
Q

Define ‘druggability’.

A

Likelihood of drug-like molecules modulating a target

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4
Q

After target ID & preclinical trials have been conducted, we reduce the number of potential drug candidates down to how many?

A

Down to 5 (started with over 10 000)!

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5
Q

Phase I clinical trials involve what type of patient population? How many?

A

Healthy (!!!); 20-80

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6
Q

Phase II clinical trials involve what type of patient population? How many?

A

Patient Volunteers; 100-300

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7
Q

Phase I vs. II vs. III… What are we monitoring in each stage?

A

I: Safety / Dosage Determination

II: Efficacy / Side Effects

III: Adverse Rxns

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8
Q

Average length (in yrs) of Preclinical & Clinical stages of drug trials?

A

6yrs (each)

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9
Q

T or F: Preclinical Trials are strongly predictive of therapeutic efficacy.

A

FALSE

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10
Q

What % of drug development processes yield licensed drugs?

A

4%

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11
Q

Major challenges of drug development?

A

1) ID’ing all targets
2) ID’ing all possible cpds
3) Drug Target Validation
4) ID’ing all bad s/e’s

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12
Q

Examples of Target ID approaches?

A

1) Data Mining - ID proteins playing role in disease-associated pathways.

2) Genetic / Genome - ID genes causing disorder or increasing disorder risk, as well as show expression level changes in dx state.

3) In-Vitro - ID targets using chemogenomic screens.

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13
Q

Example of Target ID via Data Mining we mentioned in class.

A

STAT3

-Involved in COPD (is both a target & biomarker showing strong association).

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14
Q

Describe how the PAM50 RNA Microarray is utilized in Target ID.

A

ERBB2 (ie. HER2 Transcriptome) is overexpressed in the PAM50 array, suggesting positive correlation between HER2+ Breast Cancer development & RNA Transcriptome overexpression.

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15
Q

Difference between Forward & Reverse Chemical Genetics?

A

Fwd: Identify chemical first, treat WT cells (to observe loss or gain of function), then treat mutants in order to ID targets.

Reverse: Identify targets first, then treat with multitude of different chemicals & observe phenotypic changes.

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16
Q

Approximately how many drug targets are contained within the human genome?

A

3000

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17
Q

Rank (in increasing order of confidence) the following methods for determining druggability:

Ligand Based
Structure Based
Precedence Based
Sequence Based

A

1) Sequence Based
2) Structure Based
3) Ligand Based
4) Precedence Based

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18
Q

Why do pharma companies not want to get into AB development?

A

-HC says “use less” ABs
-Short course of therapy
-Aggressive price ctrl
-Liability claims
-Drugs become obsolete quickly due to resistance development

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19
Q

Name of the act that incentivizes AB development for big pharma?

A

Pasteur Act (2022)

-Feds will pay for the true value of ABs to society vs. paying for actually prescribed volume.

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20
Q

Does chromosome number equate to organismal complexity?

A

NOOO… Humans = 46, Plants = 1260 (or even more).

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21
Q

What is the “K Value Paradox”?

A

Chromosome # DOES NOT (!!!) = Complexity.

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22
Q

What is the “C Value Paradox”?

A

Genome Size DOES NOT (!!!) = Complexity.

23
Q

What is the “N Value Paradox”?

A

Gene Number DOES NOT (!!!) = Complexity.

24
Q

Frequency of SNPs (per base pairs)?

A

1 / 300-1000

25
Q

Define “polymorphisms”.

A

Variations in DNA sequence that occur in at least 1% of the population.

26
Q

What drug causes more ED visits amongst the elderly than any other drug?

A

Warfarin

27
Q

What would happen to Warfarin levels in the body if one were to have a CYP2C9 mutation?

A

Increase… Reduced ability to metabolize Warfarin in these individuals due to impaired enzymatic synthesis.

28
Q

Compared to those with regular CYP4F2 variants, would an “A” variant of CYP4F2 need higher or lower Warfarin doses to have the same anti-coagulative effects?

A

Higher… “A” variants cannot reduce Vit. K levels properly (ie. Vit. K levels are higher), so we need higher Warfarin doses to combat this.

29
Q

If I had the “A” variant of VKORC1 gene, would I need more or less Warfarin compared to those with regular gene variant?

A

Less… “A” variants have reduced ability to recycle Vit. K (ie. Levels are lower than normal), so blood bleeds easier. Giving same Warfarin dose would OD patient and precede heightened bleed risks!

30
Q

How does Ataluren work in CF treatment?

A

Induces readthrough translation in those with Class I mutations (ie. No CFTR surface protein expression)… Corrects Nonsense Mutations!

31
Q

How does Kalydeco work in CF treatment?

A

Keeps CFTR proteins open for longer… Thus, corrects improper Chloride ion transport!

32
Q

How does Trikafta work in treatment of CF?

A

Increases CFTR protein expression (ie. Corrects F508del / Class II Mutations) & keeps CFTR channels open longer!

33
Q

What is the MOA of Antisense Oligonucleotides?

A

-Hybridize to pre-mRNA, which inhibits 5’ Cap formation (induces instability), prevents RNA splicing, and activates RNase H (which chops up unstable pre-mRNA).

-ASO presence also sterically hinders Ribosomal subunit binding (thereby preventing translation from occurring).

34
Q

ASO drugs end in what?

A

‘ersen’ or ‘irsen’

35
Q

How does Spinraza (Nusinersen) combat Spinal Muscular Atrophy?

A

Increases Exon 7 inclusion within the SMN2 (backup) gene, which increases SMN protein production.

36
Q

What is the purpose of molecular glues & how do they work?

A

-Bring two proteins together that normally do not associate…

-Allows for druggability at non-druggable sites, as well as engages body’s own immune system (via Ubiquitination) for select protein targeting / degradation.

37
Q

What are the hallmarks of cancer?

A

-Sustained Proliferative Signaling

-Evade Growth Suppressors

-Activate Invasion / Metastasis

-Immortal

-Induce Angiogenesis

-Resist Cell Death

38
Q

How does Imatinib work in CML / ALL treatment?

A

Binds in the Kinase pocket of the BCR-ABL oncoprotein, preventing ATP binding & inhibition of Tyrosine substrate phosphorylation. Thus, proliferative signaling cascade necessary for Mitosis cannot go forward.

39
Q

Give examples of BCR-ABL dependent mechanisms of Imatinib resistance.

A

1) Oncogenic Amplification… Gene expression is already too high for the drug to have effects.

2) Binding Domain Mutations… T315I (Tyrosine — Isoleucine) results in Imatinib being unable to bind to target domain.

3) P Loop Mutation… No response for either mutant form.

40
Q

Give examples of BCR-ABL independent mechanisms of Imatinib resistance.

A

1) Increased P-GP Expression… Leads to more drug efflux out of the body.

2) OCT1 Issues… Drug cannot be brought into the cell at high enough levels to have effects.

3) Alt Signal Pathway… Other signaling cascades induce cancer cell proliferation.

41
Q

What is the only available TK Inhibitor for treating brain tumors brought upon by gene fusions?

A

Entrectinib

42
Q

How do Trastuzumab & Pertuzumab differ in mechanism for treatment of HER2+ Breast Cancers?

A

T: Continual HER2 activity suppression but DOES NOT (!!!) prevent dimerization.

P: Inhibits dimerization.

-Both MABs flag mutant cells for immune destruction!

43
Q

How does Enhertu work against HER2+ Breast Cancer?

A

-Trastuzumab present in the molecule enables binding to target & constitutive suppression of HER2 activity… Payload attached (DXd) is also released into HER2+ cells, which induces DNA damage & cell death.

44
Q

What molecule does Bevacizumab inhibit?

A

VEGF (ie. Angiogenesis)

45
Q

Who are therapeutic cancer vaccines administered to?

A

THOSE WHO ALREADY HAVE CANCER… There to enhance immunotherapeutic effects, stop tumors from growing or spreading, to destroy existing cancer cells still in the body after chemo, & keeps cancer from coming back.

46
Q

Describe how the therapeutic cancer vaccine BCG works.

A

Utilizes weakened Bovine Mycobacterium after TURBT in order to stimulate the immune systems of those with Early-Stage Bladder Cancer.

47
Q

Describe how the Provenge vaccine works in treating Prostatic Cancer.

A

Extract Inactive APCs from patient blood, combine vaccine with APCs in-vitro, APCs engulf vaccine & stud their exterior with cancer proteins from vaccine, re-infuse & Active APCs “rev-up” immune system!

48
Q

Explain the premise of CAR-T Cell Therapy.

A

Remove T Cells from blood, insert CAR-T gene, T cells then express target receptors… Re-infuse & they bind cancer cell targets via their expressed receptors, leading to tumor cell death!

49
Q

What is the treatment for CAR-T Induced Cytokine Release Syndrome?

A

-Steroids
-IL-6 Blockers (ie. Tocilizumab aka Actemra)

50
Q

What are some limitations to CAR-T Cell Therapies?

A

-Very time consuming
-$$$$$$
-ID’ing surface antigens largely been unsuccessful
-Heterogeneity of tumor associated antigens

51
Q

There are two MABs that act as Immune Checkpoint Inhibitors, specifically targeting PD-1… What are they?

A

Nivolumab
Pembrolizumab

52
Q

What MAB targets CTLA-4, thereby acting as an Immune Checkpoint Inhibitor?

A

Iplimumab

53
Q

What does tumor cell overexpression of PD-L1 / PD-L2 do?

A

-Triggers T Cell Apoptosis
-Downregulates Cytokine production
-Suppresses anti-tumor response

PHAR 211 - Personalized Medicine (12 decks)

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