Chemotherapy Exam 2

Angiogenesis Inhibitor - Rationale

• tumors require new blood vessels (angiogenesis) to provide oxygen and nutrients for supporting growth beyond certain sizes

• blocking angiogenesis may block tumor growth

• Vascular endothelial growth factor (VEGF) plays a key role in tumor-induced angiogenesis

Bevacizumab (Avastin)

First-in-class VEGF inhibitor

Bevacizumab (Avastin) - Target

VEGF

• monoclonal antibody against VEGF

• VEGF is a ligand to VEGF receptor (VEGFR)

Bevacizumab (Avastin) - Mechanism 

• binds to VEGF (ligand) 

• prevents the ligands from binding to VEGFR 

• Blocks the activation of VEGFR

Bevacizumab (Avastin) - Clinical use

• in combination with chemotherapy for multiple cancers

  • lung, colon, renal, ovarian, brain cancers

• Modest effects

  • Ex: a median survival benefit of 4-5 months for patients with metastatic colorectal cancer (in combination with chemotherapy)

• Potential reasons for modest effects

  • hypoxic environment stimulates a compensatory VEGF production (feedback mechanism)

    • compromised blood supply causes a hypoxic (low-oxygen) environment

    • Hypoxic environment simulates the production of VEGF and other growth factors

  • Differential sensitivity of tumor blood vessels

  • Compromised vasculature reduces the efficiency of drug delivery to tumors

Bevacizumab (Avastin) - Side effects

hypertension, bleeding, impaired wound healing 

• VEGFR signaling affects nitric oxide synthesis (regulates blood pressure) and normal blood vessel survival and integrity 

Bevacizumab (Avastin) - Resistance

• increased level of VEGF

• Upregulation of other pro-angiogenic factors (ex: FGF) and receptor signaling

  • potential combating strategies: combining with other receptor tyrosine kinase inhibitors

Apoptosis inducer - Rationale

• Some cancer cells are particularly reliant on elevated levels of anti-apoptotic proteins to survive 

  • over-expression of anti-apoptotic proteins (ex: Bcl-2)

  • Alterations in cellular responses that increase reliance on anti-apoptotic proteins

• inhibiting anti-apoptotic proteins could restore and promote programmed cell death in cancer cells

Venetoclax (Venclexta)

First-in-class BCL-2 inhibitor

Venetoclax (Venclexta) - Target

BCL-2

• Bcl-2 is an anti-apoptotic protein

• Bcl-2 sequesters pro-apoptotic proteins (Bax and Bak), preventing them from forming dimers and inducing apoptosis

• High levels of Bcl-2 confer resistance to apoptosis

Venetoclax (Venclexta) - Mechanism 

• small molecular competitive inhibitor of Bcl-2

• BH3-mimetic

  • BH3 is a protein domain that mediates the dimerization between anti- and pro-apoptotic proteins

• Releases pro-apoptotic proteins (ex: Bax and Bak) from Bcl-2

• Allows pro-apoptotic proteins to dimerize and induce apoptosis

Venetoclax (Venclexta) - Clinical Use

• chronic lymphocytic leukemia (CLL)

  • CLL patients have a high level of Bcl-2

• AML (acute myeloid leukemia) in combination with chemotherapy

  • Bcl-2 is linked to chemotherapy resistance in AML

Venetoclax (Venclexta) - Side Effects

• tumor lysis syndrome (TLS)

  • caused by the fast breakdown of cancer cells

  • can lead to acute electrolyte and metabolic imbalances

  • potential kidney failure (requires gradual dosing and close monitoring)

  • Patients with impaired kidney function are more susceptible

• Low white blood cell count (Neutropenia)

  • due to inhibiting Bcl-2 in neutrophil precursors

    • neutrophile precursors are very sensitive to Bcl-2 level

  • increased risk of infection

PARP inhibitor - rationale

• poly ADP-ribose polymerase (PARPs) are involved in detecting and signaling cellular responses to single-strand DNA break (SSB) 

• Cancer cells with other DNA repair defects are more reliant on PARP1 to maintain DNA integrity and cell viability 

Olaparib (Lynparza) - Target

PARP1 

• Poly ADP-ribose polymerase 1 

• PARP1 facilitates DNA repair (base excision repair, BER)

Olaparib (Lynparza) - Mechanism

• small molecular inhibitor of PARP1

• Failure of BER causes an accumulation of SSB (single-strand break) and traps PARP1 on DNA

• Promotes DSB (double-strand break) during DNA replication

• Lethal to cancer cells with defects in DSB repair (ex: BRCA1/2 mutations) - unrepaired DSB is lethal to cells

Synthetic Lethality

• condition 1: PARP1 inhibition (PARP1 “defects”) - promotes DSB

• Condition 2: DSB repair defects - due to existing mutations (BRACA1/2)

  • results → Accumulation of too many DBS that become lethal to cells

Olaparib (Lynparza) - Clinical Use 

• ovarian and breast cancers with BRCA mutations 

  • BRCA genes facilitate DSB repair

Olaparib (Lynparza) - Side effect

• Myelosuppression (suppression of bone marrow where blood cells are produced)

  • hematopoietic progenitors (blood cell precursors) in bone marrow are more sensitive to DSB

  • Low white blood cell counts (increased risk of infection)

  • Low red blood cell counts (anemia)

  • patients with underlying bone marrow defects are more susceptible

Olaparib (Lynparza) -  Resistance

• PARP1 mutations that diminish inhibitor binding

• Restoration of other defective DNA repair mechanisms

  • reversion mutations on BRCA (additional mutations in BRCA that restore function)

  • Amplification of wide-type or hypomorphic (partial loss of normal gene function) BRCA

  • Becoming less reliant on PARP1 for DNA repair

Development of Targeted Therapy

• identification of specific molecular targets and vulnerabilities in the cancer cells

• Development of effective therapeutic agents against the candidate targets

• biomarkers for selecting patient populations

• toxicity limits treatment doses and duration

• diverse therapeutic resistant mechanisms