cancer 6 Flashcards
(21 cards)
five primary mechanisms for the activation of cancer genes
✅ The Five Mechanisms Summarized
1. Point Mutations (Single nucleotide changes in the DNA sequence)
mutations in Proto-oncogenes (Gain-of-function) increase the activity of proteins involved in cell proliferation (vice versa in mutations in tumor suppressor genes (loss-of-function))
- Chromosomal Translocations
A segment of one chromosome is transferred to another.
Can:
a) Moves a proto-oncogene near a highly active transcriptional region ==> Cause overexpression of a proto-oncogene (e.g., Myc in Burkitt lymphoma).
b) Fusion of two genes forms a hybrid protein with novel or enhanced functions (promoting uncontrolled proliferation) - Gene Amplification
Multiple copies of a proto-oncogene are generated.- Leads to increased protein expression (e.g., Myc, EGFR).
Insertional Mutagenesis (often implicit or combined in advanced texts but sometimes treated as a separate mechanism):
Occurs when viral DNA integrates near or within a gene.
Can activate proto-oncogenes by placing them under control of strong viral promoters.
While not always listed explicitly in your source, it’s often included in comprehensive texts.
Epigenetic Modifications (sometimes the 5th category in broader classifications):
DNA methylation or histone modification that silences tumor suppressors or activates oncogenes.
JAK2 can cause myeloproliferative neoplasms (MPNs)
JAKs are non-receptor tyrosine kinases situated on the cytoplasmic side of cytokine receptors.
Instead, they become activated only when a cytokine (e.g., EPO) binds its receptor, causing receptor dimerization and JAK auto-phosphorylation.
==> Upon activation, JAK2 initiates downstream signaling cascades (e.g., STAT, MAPK, PI3K/Akt), promoting proliferation and differentiation of hematopoietic cells.
JAK2 is a protein inside blood-forming cells that helps them grow and divide — but only when it receives the right signals (like from hormones such as erythropoietin, which tells the body to make more red blood cells).
In some people, a mutation occurs in the JAK2 gene — specifically at a spot called position 617, where the amino acid valine (V) is swapped for phenylalanine (F). This mutation is called JAK2 V617F.
🔥 What the Mutation Does (Relation to Cancer):
This mutation permanently turns JAK2 “on”, even without any growth signals.
As a result, the cell keeps growing and dividing, leading to too many blood cells being made.
This uncontrolled growth is cancer-like behavior, and it causes MPNs, which are slow-growing blood cancers
Explain how the JAK2 V617F mutation contributes to the pathogenesis of myeloproliferative neoplasms (MPNs), and name three MPNs associated with this mutation. Include the mechanism of action and relevance to targeted therapy.
A:
JAK2 is a non-receptor tyrosine kinase that transmits signals from cytokine receptors (e.g., erythropoietin, thrombopoietin receptors) to promote blood cell production.
The JAK2 V617F mutation is a point mutation where valine (V) is replaced by phenylalanine (F) at codon 617.
This mutation occurs in the JH2 pseudokinase domain, which normally inhibits JAK2 activity. The mutation disrupts this regulation, resulting in constitutive (always-on) kinase activity.
Consequently, hematopoietic cells proliferate without cytokine stimulation, leading to clonal expansion and development of MPNs.
BCR-ABL inhibitors
BCR-ABL tyrosine kinase help chronic myeloid leukemia (CML) cells to proliferate and survive —this is called oncogene addiction.
Blocking this kinase disrupts the leukemia-driving mechanisms
Imatinib is a tyrosine kinase inhibitor (TKI) that specifically blocks the BCR-ABL fusion protein.
It binds to the ATP-binding site of BCR-ABL, inhibiting its kinase activity and thus stopping downstream proliferative signaling.
Define epigenetics and describe two major epigenetic mechanisms. How can epigenetic changes contribute to cancer development? Include examples of how these changes affect gene expression.
A:
Epigenetics refers to reversible, heritable changes in gene expression that occur without alterations in the DNA sequence.
These changes affect how genes are turned on or off, playing a crucial role in cell differentiation, development, and disease.
Two Major Epigenetic Mechanisms:
1. DNA Methylation
- Involves the addition of methyl groups to cytosine residues in CpG islands (often near gene promoters).
=> Hypermethylation of promoter regions can silence tumor suppressor genes (e.g., p16, BRCA1), contributing to cancer.
=> Hypomethylation can lead to genomic instability and activation of oncogenes.
- Histone Modifications
- Post-translational changes (e.g., acetylation, methylation) to histone proteins alter chromatin structure.
Histone acetylation (by HATs) relaxes chromatin, promoting gene activation.
Histone deacetylation (by HDACs) condenses chromatin, leading to gene repression.
==> Abnormal methylation patterns are seen in various cancers.
Role in Cancer:
Epigenetic changes can inappropriately silence tumor suppressors or activate oncogenes, contributing to carcinogenesis.
These alterations are potentially reversible, making them targets for therapeutic intervention (e.g., HDAC inhibitors, DNA methyltransferase inhibitors).
dysrefgulation of miRNAs in cancer
regulate gene expression at the post-transcriptional level (after mRNA is made).
🔧 How miRNAs Work
Each miRNA binds to complementary sequences on target mRNAs (usually in the 3’ UTR).
This binding leads to:
mRNA degradation (if highly complementary)
Or inhibition of translation (if partially complementary)
The result is reduced protein production from that mRNA.
==> Cell growth, cell differentiation, Apoptosis (programmed cell death)
⚠️ miRNAs and Cancer
Tumor-Suppressor miRNAs are deleted = oncogenes escape regulation and are overexpressed.
Overexpression of Oncogenic miRNAs = they target tumor suppressor genes, silence tumor suppressor genes, promoting cancer.
Example: miRNAs that upregulate RAS in lung tumors or MYC in B-cell leukemias by indirectly reducing their suppressors.
Cancer Therapy
Cancer treatment often involves a combination of therapies, depending on the type and stage of the cancer. Here’s how the different approaches work:
🩺 1. Surgery
First line of treatment for many solid tumors.
The goal is to physically remove the tumor.
Often followed by chemotherapy or radiotherapy to destroy any remaining cancer cells.
💊 2. Chemotherapy
Uses drugs that are toxic to cancer cells, especially those that are rapidly dividing.
Unfortunately, it can also affect healthy fast-growing cells (e.g., in hair follicles, gut lining, bone marrow), causing side effects.
- DNA-alkylating agents== Damage DNA by adding alkyl groups, leading to cell death.
Anti-mitotic drugs==Block mitosis by disrupting microtubules, halting cell division.
Inhibitors of RNA synthesis==Interfere with transcription, preventing cells from making essential proteins.
Inhibitors of nucleotide interconversion==Block nucleotide metabolism, stopping DNA/RNA synthesis.
☢️ 3. Radiotherapy
Uses high-energy x-rays precisely aimed at the tumor to kill cancer cells.
Modern radiotherapy is highly targeted, aiming to minimize damage to healthy tissue while maximizing effect on tumor cells.
🧪 4. Molecularly Targeted Therapy
Based on understanding the molecular pathways (hallmarks of cancer) that drive tumor growth.
These drugs are designed to specifically target cancer-specific molecules, sparing normal cells.
==> inhibit a cancer cell pathway.
More precise than traditional chemo.
Often fewer side effects and greater effectiveness in selected patients.
Molecularly Targeted Therapy?
drugs designed to specifically block proteins or pathways that are abnormally activated or suppressed in cancer cells.
==> targeted therapy is more selective, aiming to attack only cancer-specific abnormalities.
Cancer arises due to changes in specific genes or proteins.
=> These changes lead to the activation of oncogenes (promote cancer) or the loss of tumor suppressor genes (normally inhibit cancer).
=> Targeted therapies are designed to interfere with these critical pathways.
Explain how molecularly targeted therapies exploit the increased expression or activity of oncogenes in cancer. Provide two specific examples of oncogene-driven cancers and the corresponding targeted therapies used to treat them.
Molecularly targeted therapies are designed to inhibit specific proteins that are abnormally overexpressed or hyperactivated in cancer cells, typically as a result of oncogene activation. These therapies aim to block the signaling pathways that drive uncontrolled cell proliferation, survival, and metastasis.
Oncogenes become overactive through gene amplification, point mutations, or chromosomal translocations, leading to continuous activation of growth and survival pathways. Targeted therapies act by specifically binding to these oncogenic proteins, reducing cancer cell activity while sparing normal cells.
Example 1:
Oncogene: EGFR (Epidermal Growth Factor Receptor)
Cancer: Non-small cell lung cancer (NSCLC) with EGFR mutations (e.g., L858R)
Targeted Therapy: Erlotinib or osimertinib (EGFR tyrosine kinase inhibitors)
Mechanism: Inhibits mutated EGFR, blocking downstream proliferation signaling.
Example 2:
Oncogene: BCR-ABL fusion gene
Cancer: Chronic Myeloid Leukemia (CML)
Targeted Therapy: Imatinib (a BCR-ABL tyrosine kinase inhibitor)
Mechanism: Binds to the ATP-binding site of the BCR-ABL fusion protein, inhibiting its kinase activity and halting leukemic cell proliferation.
Describe how dysregulation of apoptotic pathways contributes to cancer, and explain how molecularly targeted therapy can counteract this mechanism. Provide one example of a drug that targets an anti-apoptotic protein.
Model Answer:
In cancer, cells often acquire the ability to evade apoptosis, allowing them to survive despite DNA damage or other signals that should trigger cell death. This resistance is frequently due to the overexpression of anti-apoptotic proteins, such as Bcl-2 or Bcl-XL.
Targeted therapies can restore apoptosis by inhibiting these survival proteins, thereby reactivating the cell’s natural death pathways.
Example:
Drug: Venetoclax
Target: Bcl-2
Use: Approved for chronic lymphocytic leukemia (CLL) with high Bcl-2 expression
Mechanism: Mimics pro-apoptotic proteins, displacing them from Bcl-2, and promoting apoptosis of cancer cells.
Explain the role of angiogenesis in tumor growth and how it can be targeted therapeutically. Provide an example of a drug and its target.
Model Answer:
Angiogenesis, the formation of new blood vessels, is essential for tumors to grow beyond a small size by supplying oxygen and nutrients. Cancer cells often upregulate VEGF (vascular endothelial growth factor) to stimulate angiogenesis.
Targeted therapies inhibit this process by blocking VEGF or its receptor (VEGFR), effectively “starving” the tumor.
Example:
Drug: Bevacizumab
Target: VEGF-A (a ligand for VEGFR)
Use: Various solid tumors, including colorectal and lung cancers
Mechanism: A monoclonal antibody that binds VEGF, preventing it from activating VEGFR on endothelial cells, thereby inhibiting new blood vessel formation.
Discuss how dysregulation of the cell cycle contributes to tumor growth, and describe one molecularly targeted therapy used to address this.
Model Answer:
Cancer cells often bypass normal cell cycle checkpoints by overexpressing cyclins and CDKs (cyclin-dependent kinases). This leads to unchecked cell division, a key hallmark of cancer.
CDK4/6 inhibitors are targeted therapies that block this abnormal progression through the G1/S checkpoint.
Example:
Drug: Palbociclib
Target: CDK4/6
Use: Hormone receptor-positive, HER2-negative breast cancer
Mechanism: Inhibits CDK4/6, preventing phosphorylation of the retinoblastoma protein (Rb), thereby halting the cell cycle and slowing tumor growth.
🧬 Molecular Players of Oncogenesis
🔹 1. Oncogenes (Gain-of-Function)
These are genes that, when mutated or overexpressed, drive uncontrolled cell growth and survival.
Examples:
Receptors/kinases: PDGFR, EGFR, ALK, BCR-ABL
Signaling proteins: Ras, B-RAF, JAK2
Transcription factors: MYC
Cell cycle regulators: CDK4
✅ These are often druggable because they produce overactive proteins that can be inhibited by small molecules or antibodies.
🔹 2. Tumor-Suppressor Genes (Loss-of-Function)
These normally prevent cancer by stopping the cell cycle or inducing apoptosis. Cancer inactivates them via deletion or mutation.
Examples:
PTEN, NF1, RB, BRCA1/2, TP53
❌ Harder to target directly, since you’re dealing with missing or broken functions — instead, we target the pathways affected by their loss.
Metabolic Reprogramming PKM2 Alters glucose metabolism (Warburg effect)
Evasion of Apoptosis BCL-2 proteins Overexpression = resistance to cell death
Immortality Telomerase Maintains telomeres, enables endless division
Angiogenesis VEGF, VEGFR Promotes tumor blood supply
Metastasis SNAIL, TWIST Drive epithelial-mesenchymal transition (EMT)
Immune Evasion TGFβ, PD-L1 Suppress immune response
Inflammation IL-1, IL-4, IL-13 Promote pro-tumor environment
Epigenetics MLL1, SNF5 Modify chromatin to change gene expression
💊 What Is Druggability?
Druggability refers to whether a biological molecule (usually a protein) can be effectively targeted by a drug — typically a small molecule or biologic (like a monoclonal antibody) — in a way that alters its function to achieve a therapeutic effect.
🔬 What Makes a Target Druggable?
✅ It must bind a drug with high affinity — the protein has to have a shape or surface where a drug can “fit” and stick effectively.
✅ Binding must change the protein’s function in a way that benefits the patient (e.g., inhibiting an overactive kinase in cancer).
✅ Ideally, the target is an enzyme (like kinases, proteases) because:
= Enzymes have deep grooves or pockets (e.g., active sites).
= These are structurally well-suited to bind small molecule drugs.
⚠️ What Makes a Target Non-Druggable?
Non-druggable targets lack clear binding sites or have disordered, flexible regions, making drug binding very difficult.
These proteins (used in scaffolding, signalling, structural support etc) lack clear binding sites, making it difficult for small drugs to interfere effectively.
That’s why MYC, RAS, and many transcription factors are considered traditionally non-druggable.
from genes to medicines == desigiming drugs
🔬 1. Genetics and Genomics of Human Disease
Scientists start by studying patient populations and their DNA to identify genetic changes (mutations, amplifications, deletions) associated with disease.
These changes help pinpoint genes and proteins that might be causing or promoting disease, like oncogenes (e.g., BRAF, EGFR) or tumor suppressors (e.g., TP53).
🔁 2.Molecular Pathways & Target Validation
Once a suspect gene is found, researchers study how it works within a molecular pathway — a network of interacting proteins that regulate cell behavior (growth, death, etc.).
Molecular Pathway== (process of understanding how a disease-causing gene/protein works at the molecular level — what it interacts with, what signals it sends, and how those signals lead to disease.)
This includes target validation: confirming that interfering with this gene or protein could actually slow down or stop the disease in models (like cells or mice).
✅ Molecular pathway = understanding the mechanism
✅ Target validation = proving that targeting it is likely to work
💊 3. Drug Development
After validating the target, drugs are developed to specifically block, activate, or modify the target’s function.
These can be:
Small molecules (e.g., kinase inhibitors)
Biologics (e.g., monoclonal antibodies)
The goal is to intervene in the disease pathway in a precise way.
🧬 4. Precision Medicine
Once a drug is available, it is used to treat patients whose disease is driven by that specific target.
This is the core of precision (personalized) medicine — giving the right drug to the right patient based on their genetic or molecular profile.
🎯 Example: A patient with EGFR-mutant lung cancer would benefit from an EGFR inhibitor like erlotinib, while someone without that mutation would not.
process of target validation
Target validation is the process of proving that a specific gene or protein (the target) is:
Involved in causing the disease (especially cancer), Worth targeting with a drug, because modifying it would improve the disease outcome.
- Genetic analysis can reveal specific mutations in different cancers (e.g., HER2 in breast, EGFR in prostate, BRAF in colon).
These mutations define molecular targets for therapy.
- We use relevant lab models (cell lines, genetically modified mice) to test whether targeting the molecule:
Changes the disease phenotype
Stops tumor growth
Affects cancer signaling
🔬 Two Main Components of Target Validation:
1. Pathology Component
(tests whether a suspected cancer-driving molecule really matters (pathology)
- What happens if you silence the gene? (e.g., does cancer shrink?)
- What if you overexpress it?
- Is the gene/protein consistently present in cancer tissue?
- Is it clearly involved in carcinogenesis?
- Pharmacology Component
This evaluates whether you can actually drug the target:
==> can be effectively and safely manipulated with a drug (pharmacology).
= Can you develop a molecule that acts as: An agonist (activates), An antagonist (blocks), A reversible or irreversible inhibitor, An allosteric modulator (binds somewhere other than the main active site)
=Can the molecule bind effectively and alter the target’s function?
BRAF inibitor
Vemurafenib was developed specifically to target B-RAFV600E
a mutation that causes constant B-RAF kinase activation, leading to uncontrolled cancer cell proliferation.
In vitro: In cancer cells, vemurafenib blocks B-RAF activity → MEK & ERK are no longer phosphorylated → cell growth is reduced.
In vivo (animal models): Tumor volume shrinks dose-dependently in xenografted mice treated with vemurafenib.
🔍 Targeted Therapy = Personalized Medicine
Only patients with the V600E mutation benefit from vemurafenib → this is the core of precision medicine.
🧪 1. Roche Molecular Systems
diagnostic test identify patients with the B-RAF V600E mutation
=> so they can receive vemurafenib.
🧫 2. Real-Time PCR (Polymerase Chain Reaction)
A molecular technique that amplifies and detects specific DNA sequences.
detect the exact mutation (V600E) in the B-RAF gene.
EGFR (Epidermal Growth Factor Receptor) as a cancer target,
EGFR is a receptor tyrosine kinase (RTK) involved in controlling cell growth and survival.
When overactivated (by gene amplification or mutations), it causes uncontrolled proliferation — a hallmark of cancer.
🧪 Two Types of EGFR-Targeting Drugs:
Monoclonal antibodies (mAbs) Bind to the extracellular domain of EGFR, block ligand (EGF) binding Cetuximab, panitumumab Ends in -mab
Small-molecule kinase inhibitors Bind to the ATP-binding site in the intracellular kinase domain, block phosphorylation of downstream proteins Erlotinib, gefitinib, lapatinib, afatinib, dacomitinib Ends in -nib
two types of molecularly targeted cancer therapies:
Multi-kinase inhibitors, and
Non-kinase targeted therapies.
Multi-Kinase Inhibitors
🧠 What Are They?
Drugs that inhibit multiple tyrosine kinases at once (instead of just one).
These kinases are involved in cancer processes like:
Cell survival
Angiogenesis (blood vessel formation)
Invasion & metastasis
✅ Why Use Them?
Advantages (polypharmacology):
Targets several pathways at once → broader attack on the tumor.
Reduces resistance — if cancer finds a workaround in one pathway, others are still blocked.
Combines effects of multiple drugs in one pill.
Challenges:
Selectivity is critical — because hitting too many targets (including healthy ones) can cause side effects.
Non-cancer use (e.g., in inflammation) requires very precise targeting to avoid harm.
Non-Kinase Molecularly Targeted Therapy
🧠
These are cancer drugs that don’t target kinases, but other important proteins involved in cancer survival, immune evasion, or DNA repair.
This includes:
Immune checkpoint inhibitors (e.g., PD-1 antibodies)
Epigenetic modifiers (e.g., HDAC inhibitors)
DNA damage response inhibitors (e.g., PARP inhibitors)
🧬 What Triggers Angiogenesis in Tumors?
Hypoxia (low oxygen) in the tumor core triggers angiogenesis.
This activates HIF-1α (a transcription factor).
HIF-1α induces expression of VEGF (vascular endothelial growth factor).
VEGF then binds to its receptor (VEGFR) on nearby endothelial cells.
⚙️ How VEGFR Works:
VEGF binding causes VEGFR to dimerize and autophosphorylate.
This triggers intracellular signaling that promotes:
New blood vessel growth (neovascularization)
Cell survival, proliferation, and invasion
📌 VEGFR is a kinase, so it’s a druggable target (can be inhibited by small molecules or antibodies).
💊 Anti-Angiogenesis Therapy: Targeting VEGF/VEGFR
🔹 1. Monoclonal Antibodies
Bevacizumab (Avastin) binds VEGF outside the cell, preventing it from binding to VEGFR.
Result: VEGFR is not activated, so blood vessel formation is blocked.
Used in:
Colorectal cancer (mCRC) with chemotherapy
Breast cancer (combo with paclitaxel)
Glioblastoma (2nd-line monotherapy)
🔹 2. Kinase Inhibitors
These are small molecules that bind the intracellular ATP-binding site of VEGFR, blocking its activity.
These are multi-kinase inhibitors — they block several targets, not just VEGFR, which increases efficacy but can also cause more side effects.
