19 - Targeted Therapies & Drugs Used in Lymphoproliferative Disorders Flashcards
Cancer Chemotherapy (CCT) general types
Introduction: Targeted Therapies in Cancer
Targeted cancer therapies work by interfering with specific molecular mechanisms that allow cancer cells to grow and spread unchecked. There are three main pathways they target:
* Growth factor receptors and related intracellular
signaling cascades: Examples include epidermal
growth factor receptor (EGFR), vascular endothelial
growth factor receptor (VEGFR), Janus kinases (JAK),
and mechanistic target of rapamycin (mTOR).
* Hormonal signals (to be reviewed in other course such
as OBGYN course): Hormonal therapies counteract
tumor stimulation by hormones like estrogen in breast
cancer.
- Components of the immune system itself (Addressed
by Dr. Bottaro): Immune-targeted drugs block
inhibitory checkpoint proteins or enhance helpful
immune cells to unleash anti-cancer immunological
responses
Tyrosine-Kinase Inhibitors (TKIs): EGF Receptor (EGFR)
Introduction: Type of Mutations in TKR
Three prototypical mechanisms of genetically
altered tyrosine kinase activation as evidenced
through genetic alterations. These are:
- Gain of Function Mutations: Localized
mutations in specific exons (Exons 19, 21,
EGFR in NSCLC) - Amplifications: Increased copy number
and/or overexpression (HER1 or ERBB2 in
breast cancer) - Fusions or Translocations (such in BCR-
ABL1 fusion of ABL1 in CML)
Tyrosine-Kinase Inhibitors (TKIs): EGF Receptor (EGFR)
- Simplified representation of human epidermal growth factor receptor (HER) signaling pathway showing four members of HER family.
- HER1, HER2, and HER4 (but not HER3) each has an intracellular tyrosine kinase domain.
- EGFR1 is overexpressed in a large number of epithelial-derived cancers
- EGFR mutations enhance downstream signaling, which provides a growth and survival advantage for cancer cells and confers sensitivity to treatment with with TKIs.
- On homodimerization (e.g., HER2-HER2 pairing) or heterodimerization (e.g., HER2-HER3 pairing) of HER receptors, the tyrosine kinase domain is autophosphorylated, **leading to activation of two major downstream intracellular signaling pathways (PI3K-Akt and Raf/MEK/MAPK). **
Akt = protein kinase B ; ERK = Extracellular regulated Kinase. MEK = MAPK kinase; mTOR = mammalian target of rapamycin. PI3K = phosphatidylinositol-3-kinase; PTEN = phosphatase and tensin homolog; Raf = Raf kinase; Ras = Ras oncogene
Tyrosine-Kinase Inhibitors (TKIs): EGF Receptor 1 (EGFR1)
TKIs Mutations
* The most common activating mutations are in-frame deletions in exon 19 (del 19) between E746 and A750 (~45%) and a missense mutation in exon 21 that leads to an L858R substitution (~40%). Lung cancers with these mutations are initially sensitive to the TKIs mentioned above.
- Genotype screening for mutations in the EGFR is used to select patients who will receive TKIs and help predict prognosis
Three different generation of TKIs:
* First generation TKIs like gefitinib and erlotinib are reversible inhibitors used in EGFR-mutant non-small cell lung cancer (NSCLC).
* Second generation TKIs such as afatinib have additional EGFR family (HER) activity but increased toxicity. A common resistance mutation is EGFR T790M, reducing TKI binding.
- The third generation TKI osimertinib inhibits T790M and hasbecome standard-of-care for EGFR mutant NSCLC, showing superior efficacy and tolerability over early generation TKIs, including activity against brain metastases.
EGF Receptor 1 (EGFR1) : B-raf proto-oncogene (BRAF) gene
* BRAF functions as a serine/threonine-specific protein kinase within the mitogen-activated protein kinase (MAPK) pathway, a signaling cascade that facilitates cell growth and differentiation.
* The activation of RAF proteins initiates the activation of MEK1/2, leading to the subsequent activation of ERK.
- ERK, in turn, phosphorylates transcription factors, thereby regulating significant cellular activities.
- In colorectal cancers (CRCs), an estimated 15% to 30% are believed to originate from BRAF mutations.
- BRAF mutations are also found in melanomas and lung cancer.
* BRAF inhibitors (Vemurafenib, Encorafenib, Dafrafenib) and MEK inhibitors (Trametinib, Binimetinib) have been approved for the treatment of melanoma and thyroid cancer by the FDA
Epidermal Growth Factor Receptor 2 EGFR2/HER2
- Human Epidermal growth factor Receptor 2, c-erbB2, neu, ERBB2, CD340
- HER2 amplification correlates with more aggressive disease features including poor differentiation, heightened proliferation, lymph node spread, and in some cases, chemotherapy resistance.
- It is overexpressed in approx. 15-20% of invasive breast cancers and it’s a poor prognosis factor.
- Different mutants of HER2 wild-type are reported in breast cancer:
- (1) ∆16-HER2 has a 16 amino acid portion of the extracellular region;
- (2) P100 includes a premature stop codon which causes
truncation and only the intracellular region of the protein is translated; - (3) Herstatin includes a premature stop codon and only the intracellular region is translated.
Epidermal Growth Factor Receptor 2 EGFR2/HER2
Four HER2 tyrosine kinase inhibitors (TKIs) have been
approved for metastatic HER2+ breast cancer:
1. Lapatinib: Reversible EGFR/HER2 inhibitor. It is used to
treat Her2 positive breast cancer, trastuzumab refractory
(Target truncated form of HER2 that lacks trastuzumab
binding domain).
2. Neratinib:
3. Pyrotinib:
4. Tucatinib: Highly selective HER2 TKI combined with
trastuzumab and capecitabine recently approved as a new standard option with very good results in trials.
These agents show particular central nervous system activity,
important given the high rate of brain metastases with HER2+
breast cancer
Delayed Toxicity
Skin rash, gastroesophageal reflux
Pharmacokinetics
Major substrate CYP3A4 (drug interactions)
A 45-year-old woman with metastatic HER2+ breast cancer develops disease
progression after prior treatment with trastuzumab, pertuzumab, and T-DM1. Tumor
testing reveals truncation of the extracellular domain of HER2. Which of the following
targeted therapy options is most appropriate to treat her cancer?
A. Lapatinib
B. Neratinib
C. Pyrotinib
D. Tucatinib
Vascular Endothelial Growth Factor Receptor (VEGFR) as a target for therapy
- VEGFR2, a member of the VEGFR family, stands out as a
promising therapeutic target for tumor treatment.
* Abnormal VEGFR2 expression in neovascular tumor endothelial cells is closely associated with the initiation and progression of various tumors.
- VEGFR2 inhibitors, by impeding angiogenesis and
lymphangiogenesis, demonstrate clinical benefits against
different tumor types, despite lacking complete specificity. - Although they lack specificity for VEGFR2: Sorafenib and Sunitinib are the most widely used VEGFR2 inhibitors
Vascular Endothelial Growth Factor Receptor (VEGFR)
Inhibitors of BCR-ABL Tyrosine Kinase
- Chronic myeloid leukemia (CML) accounts for ∼20% of all leukemias diagnosed in adults
- More than 90% of adults with CML are shown to be Ph chromosome positive (Ph+)
- Philadelphia Cromosome results of a reciprocal translocation between chromosomones 9 and 22
- It is also called (Ph+) bcr-abl
Drugs used are: Imatinib, Dasatinib, Nilotinib
**Imatinib: **Inhibits Bcr-Abl and other RTKs, including PDGFR, stem cell factor, and c-kit
* Imatinib prevent ATP binding -> blocks proliferation and induces apoptosis in Bcr-Abl positive cell lines and Philadelphia chromosome positive CML
* Dasatinib and Nilotinib can be used in cells that have become resistant to Imatinib.
* oral administration; good bioavailability
* All 3 metabolized in the liver (CYP 3A4, beware of drug interactions)
The Anaplastic Lymphoma Kinase (ALK)
- The anaplastic lymphoma kinase (ALK) was first
identified in an oncogenic fusion in lymphoma. - ALK encodes a unique receptor tyrosine kinase
expressed normally in the nervous system and other
tissues, but not lymphoid cells - ALK is considered an orphan receptor, even though pleiotrophin (PTN) and midkine (MDK), both secreted growth factors, are known to bind and activate ALK downstream signaling
Activating ALK mutations in :
* pediatric neuroblastoma
* Rhabdomyosarcomas
* Gliomas
* Ewing sarcoma.
* Non-small cell lung cancer (NSCLC) (ALG+ is 4%).
They occur in younger, never or light smoker
patients, most often under age 55 at diagnosis.
The Anaplastic Lymphoma Kinase (ALK)
- In non-small cell lung cancer (NSCLC), ALK mutations
result in oncogenic fusion proteins like EML4-ALK. - This leads to constitutive activation of downstream
signaling networks including PI3K/AKT, RAS/MAPK, and
JAK/STAT that drive cancer cell proliferation and
survival.
Two Generations of Drugs
* The first-generation ALK inhibitor crizotinib showed
efficacy in ALK-positive lung cancer but was limited by
acquired resistance and inadequate brain activity.
- This prompted development of second-generation ALK
inhibitors (Alectinib, ceritinib, brigatinib) with greater selectivity and CNS penetration. - Alectinib in particular is considered a preferred initial
therapy. Approved by FDA in 2017
POLY( ADP-RIBOSE) POLYMERASE INHIBITORS: (PARP) INHIBITORS
Mechanism of Action
* Rapidly proliferating cells, including cancer cells, commonly experience endogenous single-strand breaks (SSBs).
- PARP aids in the repair of SSBs, a crucial process for cell survival.
- PARP inhibitors (Olaparib, niraparib, talazoparib and
rucaparib) disrupt the binding of PARP to DNA breaks,
hindering the repair of replication-associated DNA damage. - Unrepaired SSBs can progress to toxic double-strand breaks (DSBs).
- Homologous recombination (HR) serves as the primary pathway for repairing these DSBs during cell replication.
* BRCA1 and BRCA2 proteins help recognize DNA damage and recruit other proteins to repair double-strand breaks by homologous recombination
Targeting Chronic Lymphocytic Leukemia (CLL)
- CLL is characterized by an accumulation of monoclonal, mature, B cells in the peripheral blood, bone marrow, and secondary lymphoid organs.
- The B cell receptor (BCR) expressed on the malignant cells in CLL contributes to disease pathogenesis by providing signals for survival and proliferation (e.g activation of bcl-2)
- In CLL there is accumulation of B cells that do not undergo apoptosis by overexpression of signaling proteins (e.g. bcl-2 an anti-apoptotic protein)
Therapeutics:
1. Cancer Chemotherapy (CCT) Drugs:
Fludarabine (Purine analog); Chlorambucil (Alkylating agent), etc
2. Multiple Combination CCT Protocols
Fludarabine, cyclophosphamide, and rituximab (FCR);
Pentostatin, cyclophosphamide, and rituximab (PCR), etc
3. Antibodies:
Rituximab, Alemtuzumab, etc (target CD52)
Ofatumumab (Arzerra), Obinitizumab (target CD20)
4. Cell signaling inhibitors that specifically target the signaling
pathway initiated following B cell antigen receptor (BCR)
* Ibrutinib, ONO-4059, ACP-196 (BTK inhibitor)
* Idelalisib, Duvelisib, TGR-1202, etc (PI3K-δ inhibitor)
* Fostamatinib, and Entospetinib (Syk Inhibitor)
* Venetoclax (bcl-2 inhibitor)
5. Immunomodulators
* Glucocorticoids: Prednisone (prior lecture)
* Lenalidomide
- Cyclin-Dependent Kinase (CDK) inhibitors (Alvocidib, Dinacibid, etc)
- Others: Radiation, Bone marrow or peripheral stem cell transplantation (clinical trial), CART therapy (clinical trial)
Targets in CLL: Bcl-2 (B-cell lymphoma 2)
- The anti-apoptotic protein Bcl-2 is frequently overexpressed in lymphoid malignancies
- Bcl-2 is overexpressed in ~80% of CLL cases
- Bcl-2 prevents Bax/Bak pro-apoptotic executioner molecules, allowing cancer cells to evade programmed cell death.
- Therefore, high levels of BCL-2 in CLL cells which makes them resistant to apoptosis
- The selective Bcl-2 inhibitor venetoclax displaces pro-death factors bound to Bcl-2, restoring sensitivity to apoptotic signaling.
- By blocking aberrant Bcl-2 activity enabling malignant lymphocyte survival, venetoclax elicits anti-tumor efficacy, including for relapsed chronic lymphocytic leukemia
C
Immunomodulators: Lenalidomide (LEN)
- Lenalidomide (LEN), a derivative of thalidomide, is an immunomodulatory drug with potent antineoplastic, anti-angiogenic, and anti-inflammatory properties.
- It acts by a novel drug mechanism—modulation of the cereblon (CRBN).
- The central target molecule for LEN is cereblon (CRBN). CRBN interacts with DNA binding protein 1 (DDB1) and together with cullin-4A (CUL4) and regulator of cullins 1 (ROC1) to form the CRL4 E3 ubiquitin ligase complex (CRL4).
* This triggers an increase in ubiquitination and subsequent degradation of the two transcription factors Ikaros (IKZF1) and Aiolos (IKZF3)
* The subsequent proteasomal degradation of these transcription factors leads to the death of multiple myeloma cells - This mechanism of action demonstrates the potential for the development of new therapies that modulate ubiquitination.
* Lenalidomide could be teratogenic
Targeting Modified Protein Processes: L-Asparaginase
- L-Asparaginase is used in the treatment of leukemias,
specifically ALL because leukemia cells require huge amounts of asparagine to keep up with their rapid malignant growth -
When asparagine levels are low, asparagine synthetase
(ASNS) catalyzes transamination of glutamine to aspartate, resulting in production of glutamate and asparagine.
* Acute lymphoblastic leukemia (ALL) cells generally exhibit little to no detectable ASNS expression, which makes ALL cells auxotrophs for asparagine and renders them particularly sensitive to asparagine depletion.
* Auxotroph is a mutant organism that requires a particular additional nutrient which the normal strain does not.
- Finally, Asparaginase induces the apoptosis in leukemic cells.
* Adverse Effects: Hepatotoxicity, increased risk of bleeding and clotting
Proteasome inhibitors
- Proteasomes are large cellular protein complexes that
degrade ubiquitinated proteins. - Damaged, misfolded or unneeded proteins are labelled by enzymatic conjugation with the protein ubiquitin.
- The ubiquitinated complex is then destroyed in the
proteasome by proteolysis.
* This pathway is dysregulated in some malignant cells leading to increased proteasome activity and resistance of the cell to apoptosis.
- Targets include: cell cycle regulatory proteins, whose timely
destruction is vital for controlled cell division. - Drugs that tarfget the proteosme:
- First Generation: Bortezomib (reversible)
- Second Generation: Carfilzomib (CFZ, irreversible),
Ixazomib, Omacetaxine
* Multiple myeloma cells are particularly sensitive to proteasome inhibition, which delays tumor growth
Histone Deacetylase (HDAC) Inhibitors
Summary of Targeted therapies in lymphoproliferative disorders
