Targeted Therapies

Attack proliferative and metabolic pathways unique to malignant cells

What is one mechanism by which targeted therapy molecules work, concerning pathways?

Identify unique signatures of malignant cells and call on the immune system to destroy these cells

What is one mechanism by which targeted therapy molecules work, involving the immune system?

Targets rapidly dividing cells (mostly cancer cells)

How does chemotherapy primarily work?

Hair loss, intestinal damage, nausea

What are common side effects of chemotherapy?

Cancer cells develop resistance to chemotherapy, not specific

What are limitations of chemotherapy?

Targets Proteins required for cancer growth

How does targeted therapy primarily work?

Liver problems, diarrhea, skin rash

What are common side effects of targeted therapy?

Cancer cells develop resistance

What is a limitation of targeted therapy?

Uses our immune system against cancer

How does immunotherapy primarily work?

Autoimmune effects

What are side effects associated with immunotherapy?

Tailored and expensive

What are limitations of immunotherapy?

Sustaining proliferative growth

What cancer hallmark involves continuous cell multiplication?

Evading immune destruction

What cancer hallmark involves avoiding attack by the body's defense system?

Aerobic glycolysis

What metabolic process is listed under the hallmark of Deregulating metabolism?

anti-CTLA4 mAb

What is an example of a therapeutic strategy for Evading immune activating signaling suppressors?

BH3 mimetics

What is an example of a therapeutic strategy for Resisting cell death?

Telomerase Inhibitors

What is the therapeutic strategy targeting Enabling replicative immortality?

PARP inhibitors

What is a therapeutic strategy listed for Genome instability & mutation?

Selective anti-inflammatory drugs

What is a therapeutic strategy for Tumor promoting inflammation?

Inhibitors of angiogenesis

What therapeutic strategy targets Inducing angiogenesis?

Inhibitors of invasion & metastasis

What therapeutic strategy targets Enabling invasion & metastasis?

EGFR inhibitors, HER2 antibodies

What are examples of therapies targeting Sustaining proliferative signaling?

Inhibit cell-cycle regulators

What therapeutic strategy targets Evading growth suppressors?

CDK4/6 inhibitors

What is an example of a therapy that inhibits cell-cycle regulators to target Evading growth suppressors?

Promote apoptosis

What therapeutic strategy targets Resisting cell death?

BCL-2 inhibitors

What is an example of a therapy that promotes apoptosis to target Resisting cell death?

Block angiogenesis

What therapeutic strategy targets Inducing/accessing vasculature?

VEGF inhibitors

What is an example of a therapy used to block angiogenesis?

Disrupt tumor metabolism

What therapeutic strategy targets Deregulating metabolism?

Glycolysis inhibitors; metabolic modulators

What are examples of therapies used to disrupt tumor metabolism?

Target telomerase pathways (emerging)

What therapeutic strategy targets Enabling replicative immortality?

Under clinical investigation

What is the current status of therapies targeting Enabling replicative immortality (telomerase pathways)?

Unleash T-cell response

What therapeutic strategy targets Avoiding immune destruction?

Checkpoint inhibitors (PD-1, PD-L1, CTLA-4)

What are examples of therapies used to unleash the T-cell response to combat Avoiding immune destruction?

Sensitize tumors to immune or targeted therapies

What therapeutic strategy targets Unlocking phenotypic plasticity / Epigenetic reprogramming?

Emerging combination strategies

What type of strategies are used to target Unlocking phenotypic plasticity / Epigenetic reprogramming?

PARP inhibitors in BRCA-mutant

What is a specific example of a therapy related to Genomic instability & mutation?

Monoclonal antibodies, Drug-antibody conjugate, Small molecule inhibitors, Signaling inhibitors, Angiogenesis inhibitors, Hormonal Therapy, Immune checkpoint inhibitors, Immunotherapy

Name the major classes of targeted therapy listed.

Direct killing, Toxin, BiTE, Phagocytosis, ADCC, Blockage of inhibitory checkpoint molecules

List the mechanisms of action of Monoclonal Antibodies.

Toxin

Monoclonal antibodies can be conjugated to what substance for targeted delivery?

Phagocytosis

What mechanism of mAb action involves engulfment by immune cells?

Blockage of inhibitory checkpoint molecules

How do some mAbs act on the immune system regarding checkpoints?

Fc-receptor

What receptor on a Macrophage is involved in ADCC?

EGFR activation

What initiates the activation of downstream signaling pathways in an epithelial cell?

Proliferation, Survival, Vascular Permeability, Lymphangiogenesis, Migration

What are downstream cellular effects of EGFR activation listed?

HSC Survival, Monocyte Chemotaxis, Inhibition of DC Maturation

What are other listed downstream cellular processes related to EGFR activation?

PD-L1

What molecule binds to PD-1 and inhibits T cell killing of a tumor cell?

Blocking PD-L1 or PD-1

What action allows T cell killing of a tumor cell?

CD52

What is the antibody target for alemtuzumab?

B-cell chronic lymphocytic leukemia

What is the indication for alemtuzumab (targeting CD52)?

PD-L1

What is the target of atezolizumab and avelumab?

Metastatic non-small cell lung cancer, Urothelial carcinoma

What are the indications for atezolizumab?

Metastatic Merkel cell carcinoma

What is the indication for avelumab?

VEGF

What is the target of bevacizumab?

Metastatic colorectal cancer

What is the indication for bevacizumab?

CD19

What is the target of blinatumomab?

Precursor B-cell acute lymphoblastic leukemia

What is the indication for blinatumomab?

CD30

What is the target of brentuximab vedotin?

Hodgkin lymphoma, Anaplastic large-cell lymphoma

What are the indications for brentuximab vedotin?

EGFR

What is the target of cetuximab?

Metastatic colorectal carcinoma

What is the indication for cetuximab?

CD38

What is the target of daratumumab?

Multiple myeloma

What is the indication for daratumumab, elotuzumab, and Panobinostat?

IL4RA

What is the target of dupilumab?

Atopic dermatitis, asthma

What are the indications for dupilumab?

SLAMF7

What is the target of elotuzumab?

CD33

What is the target of gemtuzumab ozogamicin?

Acute myeloid leukemia

What is the indication for gemtuzumab ozogamicin?

CD20

What is the target of ibritumomab tiuxetan, obinutuzumab, ofatumumab, and rituximab?

Relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma

What is the indication for ibritumomab tiuxetan?

CD22

What is the target of inotuzumab ozogamicin?

Precursor B-cell acute lymphoblastic leukemia

What is the indication for inotuzumab ozogamicin?

CTLA-4

What is the target of ipilimumab?

Metastatic melanoma

What is the indication for ipilimumab, nivolumab, and pembrolizumab?

EGFR

What is the target of necitumumab?

Metastatic squamous non-small cell lung carcinoma

What is the indication for necitumumab and nivolumab?

PD-1

What is the target of nivolumab and pembrolizumab?

Chronic lymphocytic leukemia

What are the indications for obinutuzumab and ofatumumab?

Metastatic breast cancer

What is the indication for pertuzumab and trastuzumab?

HER2

What is the target of pertuzumab and trastuzumab?

VEGFR2

What is the target of ramucirumab?

Gastric cancer

What is the indication for ramucirumab?

B-cell non-Hodgkin's lymphoma

What is the indication for rituximab?

Infusion reactions / Allergic reactions, Cytokine release syndrome, Fever, chills, Weakness, headache, Nausea, vomiting, diarrhea

What are general adverse effects associated with monoclonal antibodies?

Cardiomyopathy

What specific adverse effect is associated with trastuzumab?

RTK (ABL, KIT, POGFR, HER, ALK, ROS, MET, FGFR, TRK, FLT3, CSFIR, VEGFR)

What family of targets do many small molecule inhibitors address?

ABL, KIT, PDGFR, SCF

What are the primary targets of Imatinib (Gleevec)?

Ph-positive CML, Ph-positive ALL, PDGFR rearrangements MDS/MPD, ASM, HES, CEL, DFSP, KIT-positive GIST

What are the indications for Imatinib, Dasatinib, and Nilotinib?

KIT, PDGFRA mutations, PDGFRB, TIE2, VEGFR2, BRAF

What are the targets of Ripretinib (Quinlock)?

GIST

What is the indication for Ripretinib (Quinlock)?

EGFR and HER family

What are the targets of Gefitinib (Iressa)?

NSCLC

What is the indication for Gefitinib (Iressa)?

Cyclin D

Which protein is involved in the G1/S checkpoint of the Cell Cycle shown in the diagram?

NSCLC with EGFR 19del or L858R, pancreatic cancer

What are the indications for Erlotinib (Tarceva)?

NSCLC with nonresistant EGFR mutations, squamous NSCLC

What are the indications for Afatinib (Gilotrif)?

NSCLC with EGFR 19del or L858R, NSCLC with T790M positive

What are the indications for Osimertinib (Tagrisso)?

HER2-positive breast cancer

What is the indication for Lapatinib (Tykerb), Neratinib (Nerlynx), and Tucatinib (Tukysa)?

EGFR and HER family

What are the targets shared by Erlotinib, Afatinib, Osimertinib, Lapatinib, Neratinib, and Tucatinib?

ALK, HGFR, c-Met, ROS1, RON

What are the targets of Crizotinib (Xalkori), Ceritinib (Zykadia), Alectinib (Alecensa), Brigatinib (Alunbrig), and Lorlatinib (Lorviqua)?

ALK- or ROS1-positive NSCLC, ALK-positive anaplastic large cell lymphoma

What are the indications for Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib?