Hormonal and TK Targeting Therapies

These genes encode for tumor suppressing function, mutations supress these genes and lead to a 50-80% risk of developing breast cancer, inherited gene mutation that causes 5-10% of breast cancer

HER2 is human growth factor receptor 2, and helps control cell growth. HER2+ breast cancer has overexpression of HER2, making it a faster proliferator and more agressive, but allowing for more specific HER2 targeting treatments.

Also known as ErbB2

Estrogen receptor

ER+ need estrogen to grow and can be treated by drugs that block estrogen from binding

ER- don't have estrogen receptors and don't need estrogen to grow

About 70% of breast cancer is ER+, but it can mutate to become ER-

Selective estrogen receptor modulators

Selective estrogen receptor downregulators

They look like estrogen and bind to estrogen receptors better than estrogen, blocking estrogen binding and inactivating the receptor. Target specifically ER+ breast cancer so fewer side effects and often used as a long term maintenance medication. Since they bind to ER stronger than estrogen does, they can be used in both pre and post menopausal women as the high levels of estrogen in pre menopausal women don't have much impact on their efficacy.

Tamoxifen, the first SERM
Raloxifene

Tamoxifen

Raloxifene

It is the product of cytochrome P450, which converts androstenedione and testosterone into estrogens. Men and women have the same hormonal pathway, but the action of aromatase further converts male sex hormones into female ones.

They inhibit the action of aromatase, preventing the creation of estrogen.

Post-menopausal women, pre menopausal women have too much estrogen production to effectively stop

They are steroidal and look like the androstenedione that aromatase normally binds to, inhibiting it by irreversably binding with a covalent bond. Many side effects and not commonly used anymore.

Non steroidal, they reversably bind to the heme iron group of aromatase. CYP inhibitors, can lead to side effects and interactions.

Anastrozole and letrozole, these are third generation type two aromatase inhibitors that are very potent and selective, less side effects

Anastrozole and letrozole, the third generation type two aromatase inhibitors. Note the 1, 2, 4 nitrogren ring structure

Depriving prostate cancer cells of androgen, which leads to their death. High incidence of sex related side effects due to lack of androgen, development of feminine characteristics, etc, so treatment not always used depending on patient age and risk factors.

Luteinizing hormone-releasing hormone/Gonadotropin releasing hormone agonists

Androgen receptor blockers (similar to SERMs but fopr androgen)

LHRH is released from the hypothalamus, which causes the anterior pituitary to release FSH, which stimulates the testis to produce testosterone.

LHRH agonists look like LHRH but are more resistant to degridation by replacing gly6 with a d-configuration amino acid and so cause more release of FSH than LHRH does, leading to even greater testosterone production. However, this increased agonism eventually leads to desensitization, leading to long term decrease in testosterone levels. Lag time associated with desensitization.

Leoprolide
Goserelin

The androgen receptors will change shape to no longer bind AR blcokers but still bind androgens.

It binds to P450(17a), which is involved in testosterone synthesis. Similar to aromatase inhibitors, where it blocks production of the hormone.

Flutamide
Cyproterone acetate
Enzalutamide

Newest AR blocker that has shown significant survival benefit

Flutamide

Cyproterone acetate

Abiraterone

Enzalutamide

They add (kinases) or remove (phosphatases) a phophorus group to an oxygen on an amino acid. Specifically in this context, they target either tyrosine, or serine and threonine. Kinases tend to be oncogenes, turning on growth factors, while phosphatases tend to be tumor supressor genes.

Receptor and non-receptor tirosine kinases. RTKs have a transmembrane region with an extracellular ligand binding domain, NRTKs don't.

They mimic ATP, binding to R/NRTKs instead of ATP and stopping signaling. While all kinases bind to ATP, there are enough conformational changes in tyrosine kinases to make the action of these drugs specific to inhibiting them.

They target the ligand proteins that binds to RTKs

Because monoclonal antibody's target the ligand that binds to the extracellular binding domain, which isn't present with NRTKs.

It is a monoclonal antibody which targets HER2 (ErbB2)

It is a monoclonal antibody which targets EGFR (ErbB1)

It is a mutation which is caused by a translocation between chromosomes 9 and 22. This creates the philadelphia chromosome which juxtaposes the sequences of bcr, a harmless protein which is found in very high levels within cells, and c-abl, which encodes for an NRTK, which are oncogenes. This leads to rapid production of NRTKs, causing rapid cell growth and proliferation. This mutation is found in 95% of chronic myelogenous leukemia (CML) patients.

A NRTK caused by the philadelphia chromosome mutation

Bcr-Abl kinase, an NRTK mutation commonly found in CML (chronic myelogenous leukemia).

Very effective and with minimal side effects since Bcr-Abl kinase is not found in healthy cells.

ATP mimic, binds to the ATP binding site on Bcr-Abl kinase and antagonizes it, preventing signaling

Since the drug has a very high specificity, it is very effective against it's target with minimal side effects. However, in patients that don't have this philadelphia chromosome mutation, or if there is further mutation in this receptor, efficacy becomes very low. High specificity leads to little side effects, but also leads to a narrow range of efficacy.

Not many since they are very selective to cancer cells.
Reduction in Ph chromosome positive cells
Also inhibits c-Kit receptor and PDGFR
Inhibition of c-Kit allows it to also be used in patients with gastrointestinal stromal tumors (GIST)

An amino acid in the active site that gives specificity about what a receptor will bind to, and can determine efficacy and specificity of kinase inhibitors.

In the T315I mutation, a Thr gatekeeper residue in the Bcr-Abl kinase can mutate to Ile, which majorly lowers the affinity for imatinib. Since this is an easy single mutation, drug resistance to imatinib is relatively high.

Found in 10-20% of patients with imatinib treatment failure, this mutation keeps the kinase constantly activated.

A second generation version of imatinib, which inhibits several tirosine kinases.
This can inhibit the active form of the enzyme as well, kicking out ATP, while imatinib can only bind to inactivated kinases
About 20x more potent than imatinib
Still doesn't work against T315I

Another second generation imatinib, which also targets several tirosine kinases
Like imatinib, it only targets the inactive form of th enzyme
While it does show promise against many imatinib resistant kinases, the T315I mutation still is resistant

A 3rd generation Bcr-Abl inhibitor which is effective against the T315I mutation

Another 3rd generation Bcr-Abl inhibitor for CML which works against the T315I mutation.

The Bcr-Abl NRTK mutation, caused by the philidelphia chromosome which is found in many CML patients

Imatinib

Dasatinib
Nilotinib
More potent and effective against some resistances. However less selective and still not able to get around the T315I mutation

Ponatinib
Bosutanib
Effective against both wild type and T315I mutatant Bcr-Abl

epidermal growth factor receptor, it is an RTK (meaning a extracellular ligand binding and intracellular tyrosine kinase domain), often overexpressed in cancer cells and leading to increased growth/proliferation.

Frequently overexpressed in NSCLC (non-small cell lung cancer)

1st generation EGFR inhibitors. ATP mimics which target EGFR, binding to and reversably inhibiting them. Erlotinib more commonly used, gefitinib has more side effects such as lung disease.

Found to not work with most patients in trial, however certain subgroups, such as women and east asian descent, had very high efficacy. Only works well in certain mutations which cause EGFR to become more active and causes the cells to become more dependent on it, do genomic sequencing is essential to effective use.

T790M, which increases EGFR's affinity for ATP over the inhibitors. This makes it bind much more quickly to ATP than to the inhibitors and therefore makes it much more likely that it will bind to ATP whenever it is unbound. Resistance appears in almost 100% of patients after extended use.

The T790M mutation increases affinity for ATP, therefore making it more likely to bind to ATP, and since gefitinib and erlotinib are reversable, even if one of the EGFRs binds to them, it will eventually release it and continue its function being much more likely to grab ATP again. However, with an irreversable inhibitor, it will eventually bind to one, even though binding to ATP is much more likely, and then it will be permanently shut down, making irreversable inhibitors effective even against the T790M mutation.

**Note, we don't have to know any specific irreversable EGFR inhibitors for the exam

A kinase inhibitor, "pyrimidine structure"

Not all the kinase inhibitors have this structure, but if he asks us to identify a kinase inhibitor on the exam it will have this, and we won't have to identify it any further than it being a kinase inhibitor

ATP mimic that inhibits HER2, effective against HER2 positive breast cancer

The formation of new blood vessels from existing ones

Vascular epidermal growth factor, a ligand that binds to VEGFR (VEGF receptor), triggering angiogensis. Used by cancer cells to support faster and larger growth using nutrients brought in from this new vasculature.

Kidney cancer, which is highly vascularized

TK inhibitor that blocks VEGFR and some other TK receptors.

Hits VEGFR1, 2, and 3

Blocks vascularization and kills tumors from the inside out, as the outermost cells are the ones with the most access to blood supply.

A microtubule associated protein (EML4) fused with the kinase domain of ALK, present in 3-13% of NSCLC (non-small cell lung disease).

ATP mimic that binds to and inhibits ALK, halting proliferation of NSCLC (non-small cell lung cancer) lines with an ALK infusion

An RTK which activates the Ras/RAF/MEK/ERK signaling pathway and is frequently mutated in melanoma.

BRAF V600E, which destabilizes the inactive form of B-RAF and causes it to be activated. 500x activated compared to non-mutated BRAF.

An ATP mimic that targets BRAF V600E, inhibiting it's activation. Effective against melanoma, with little impact on other kinases.

Has raf in the name (B-RAF inhibitor)

ATP mimics: Look like ATP in order to bind to and antagonize TK. Can target all types of TK, whether RTK or NRTK, as all TK use ATP. ATP mimic drugs are specific, only inhibiting certain tyrosine kinases. For this exam, we have to know Bcr-Abl inhibitors, EGFR inhibitors, HER2 inhibitors, VEGFR inhibitors, ALK inhibitors, and BRAF V600E inhibitors, which are all different classes of ATP mimicking drugs.

1st generation Bcr-Abl inhibitors: ATP mimics which bind to Bcr-Abl, a mutated kinase commonly found in CML
2nd generation Bcr-Abl inhibitors: More potent less selective than first generation, effective against some drug resistant CMLs, but not against the T315I mutation
3rd generation Bcr-Abl inhibitors: Effective against T315I mutations

1st generation EGFR inhibitors: ATP mimics which reversibly bind to EGFR, which are highly expressed in some cancers such as NSCLC. Even within these types of cancer, these inhibitors are only effective in patient populations with specific mutations, so genomic testing is required.
2nd generation EGFR inhibitors: ATP mimics which *irreversibly* bind EGFR, making them effective against the T790M mutation (don't need to know specific examples)

HER2 inhibitors: ATP mimics which bind to HER2, effective against HER2+ breast cancer

VEGFR inhibitors: ATP mimics which bind to VEGFR, effective against cancers that are highly vascularized, such as kidney cancer

ALK inhibitors: ATP mimics which bind to ALK, Effective against ALK positive forms of NSCLC

BRAF V600E inhibitors: ATP mimics which bind to BRAF with the V600E mutation, effective against melanoma with the BRAF V600E mutation

Monoclonal antibodies: Target ligands that bind to the extracellular domain of RTK, antagonizing their activation. Can only be used against RTKs, as NRTKs don't bind to ligands.

SERMs: Selective estrogen receptor modulators, which mimic estrogen and bind to estrogen receptors, antagonizing their action. Effective against ER+ breast cancer
SERDs: Selective estrogen receptor downregulators, limit expression of estrogen receptors, not commonly used/don't need to know any specific drugs

Type 1 aromatase inhibitors: Inhibits the action of aromatase, which turns male sex hormones into female ones. Mimics androstenedione which aromatase normally converts, covalently binding to aromatase and irreversably inhbiting it. Many side effects so not commonly used anymore/don't need to know any specific drugs
Type 2 aromatase inhibitors: Non-steroidal aromatase inhibitors, which reversably bind to heme iron to inhibit aromatase. Effective against ER+ breast cancer in post-menopausal women where estrogen production has already slowed down enough for aromatase inhibitors to have an impact.

LHRH agonists: luteinizing hormone releasing hormone agonists which initially stimulates testosterone production, however after a lag period will cause desensitization and a massive decrease in testosterone production. Effective against prostate cancers which are typically testosterone dependent.

AR blockers: Androgen receptor blockers, which bind to and inhibit androgen receptors, effective against prostate cancers which are typically testosterone dependent.

Abiraterone: Binds to P450(17a), inhibiting it and blocking the synthesis of testosterone. Effective against testosterone dependent prostate cancers.

SERMs: Tamoxifen, Raloxifene

Type 2 Aromatase Inhibitors: Anastrazole, Letrozole

LHRH agonists: Leuprolide, Goserelin

Abiraterone: Abiraterone

AR Blockers: Flutamide, Cyproterone acetate, Enzalutemide (newest with survival benefit)

Monoclonal antibodies: Trastuzumab (against HER2), Cetuximab (against EGFR)

1st Generation Bcr-Abl Inhibitors: Imatinib
2nd Generation Bcr-Abl Inhibitors: Dasatinib, Nilotinib
3rd Generation Bcr-Abl Inhbitors: Ponatinib, Bosutinib

1st Generation EGFR Inhibitors: Erlotinib, Gefitinib

HER2 Inhibitors: Lapatinib

VEGFR Inhibitors: Sunitinib (Sutent)

ALK Inhibitors: Crizotinib

BRAF V600E Inhibitors: Vemurafenib