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Advances in Oncology
Justin M. Markow, DO
Coastal Cancer Center
The Human Genome
“It will revolutionize the diagnosis,
prevention and treatment of most, if
not all, human diseases.”-Bill Clinton.
This proved more difficult than
anticipated.
Complexity of Genome
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Not just the DNA code.
Epigenetic modifications: Acetylation of histone
proteins and methylation of promoter sequences.
Small miRNA bind with RNA and alter gene
expression.
Post-transcriptional and translational modification
alters cellular phenotype.
After transcription
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Alternative splicing creates multiple protein
products from one gene.
Chaperone proteins assist with protein folding to
ensure proper function.
The proteome: Range of proteins created from DNA.
Allows for many permutations.
There are many more variables.
History
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Mustard gas was 1st used in WWI.
A German air raid on Bari, Italy in WWII damaged
nearby cargo ship holding Nitrogen Mustard.
Exposed soldiers were noted to have lymphopenia
and lymph node regression.
Researchers at Yale studied this association.
Chemotherapy
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For next 40-50 years treatment was non specific;
Agents damaged malignant and non-malignant cells
alike.
Damages hair follicles, GI tract, bone marrow.
Alkylating agents, topoisomerase inhibitors,
microtubule inhibitors, antimetabolites.
Target DNA replication, DNA uncoiling, cell
division, and nucleotide production.
Chemotherapy Action
Cell Cycle
New Era
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Tamoxifen approved in 1990s.
SERM - ER antagonist at breast tissue but agonist
elsewhere. Alters gene transcription.
Cells slip into G0 and G1 phases of cycle.
Cytostatic.
Reduces recurrence of breast cancer by 40%.
Tyrosine Kinases
CML
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t(9;22) results in a fusion product of ABL1 and
BCR proteins.
Constitutively active TK, which ddrives cellular
proliferation.
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95% of CML cases
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Five year survival was 30%.
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Most patients progressed to blast phase/AML.
CML
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The only cure is an Allogeneic Transplant.
Infections, GVHD, thrombosis, rejection/relapse.
FDA approved Imatinib in 2001. TKI of the BCRABL protein.
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A model for future cancer drug development.
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Five year survival rates are now 89%-95%.
CML
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Not a “cure” in technical sense of the word.
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BCR-ABL is the pathogenic step.
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Clone is “addicted” to oncogene.
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Not the case with most malignancies.
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Few diseases have a single integral pathogenic
lesion.
Oncogenesis
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5-7 mutations in tumor suppressor and oncogenes to
develop a malignancy.
Suppress apoptosis and enhance cellular
proliferation.
Mutated TS shuts off apoptotic defense. AR (two
copies required).
Mutated Oncogenes drive cellular growth. AD (one
copy needed).
Targeted Therapy
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TKIs and other small molecule inhibitors,
monoclonal antibodies, vaccinations, and immune
based therapies.
EGFR is a transmembrane TK integral for cellular
proliferation.
Activated in 30% of epithelial cancers.
Mutated in 10% of lung adenocarcinomas (exon
21>exon 19).
EGFR Inhibitors
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Erlotinib: Binds reversibly to ATP binding domain.
Increases OS and PFS in 2nd line (12.4 vs 11 mos).
Doubles PFS (9.4 vs 5.2 mos) in mutated patients.
T790M and activation of MET oncogene are
pathways of resistance.
EGFR Inhibitors
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Afatinib: Irreversible TKI. PFS and RR in LUXLung 3 trial.
Crizotinib: Inhibitor of ALK fusion protein.
4% of NSCLCs have translocation between EML4
and ALK. ORR 60%.
Small Molecule Inhibitors
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MTOR is intracellular protein.
Leads to increased cyclin D and HIF-1a. These are
required for cell growth, survival, and angiogenesis.
RCCs have decreased degradation of HIF-1a via
mutated VHL.
MTOR inhibitors in RCC, Breast cancer,
Neuroendocrine tumors, Lymphomas,
Small Molecule Inhibitors in RCC
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Everolimus and Temsirolimus are active in RCC.
Sunitinib: A multi-TKI (VEGF, PDGFR, KIT, RET,
FLT3) with survival advantage in RCC. Also used in
neuroendocrine tumors, GIST, Leukemia.
Pozopanib: Muti-TKI with activity similar to sutent
in RCC but better tolerability. Also used in sarcoma.
JAK STAT Pathway
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Jak
JAK Inhibition
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Mutated in 50% of ET and MF, > 90% PCV.
Ruxolitinib: a JAK 1 and 2 inhibitor. Reduced spleen
volume > 35%, reduced risk of death by 52%, and
reduced symptoms in MF (COMFORT trial).
Activity in wt JAK patients also.
Now approved in PCV for intolerant or resistant to
Hydrea.
Solid Tumors?
Other Small Molecule Inhibitors
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Vemurafenib: BRAF inhibitor.50-60% of melanomas
have a BRAF mutation. ORR 80%, lasts only 8-9
months.
Ibrutinib: BTK inhibitor. Needed for survival and
growth of B cells. Active in CLL, MCL, DLBCL.
ORR from 60-70% in pretreated patients.
Also p13/AKT, PARP, MEK, MET inhibitors,
miRNAs, CDK inhibitors.
Monoclonal Antibodies
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Rituxan: MAB targets CD20 antigen present on
most B cells. FDA approved in 1997.
Induces ADCC (NKs, Macrophages, Neutrophils) ,
CDC, and apoptosis.
Increased PFS and OS in B-cell malignancies.
Rituxan
Other Antibodies
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Erbitux: MAB targets EGFR. Survival advantage in
KRAS wt Colon cancers. In head and neck cancers
also.
Traztuzumab: MAB against Her2Neu receptor.
Survival advantage in MBC and Gastric Cancer.
Reduces risk of recurrence in BC by 10%.
Pertuzumab: MAB blocks dimerization of Her2Neu
receptor. Improves PFS in MBC. Greater RR in
neoadjuvant setting (Tryphaena trial).
Pertuzumab
Antibody Drug Conjugates
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Bound to cytotoxics via a linker molecule, allowing
targeted and efficent delivery.
Traztuzumab emtansine: Traztuzumab and a tubulin
inhibitor. Demonstrated OS and PFS advantage in
H2N+ MBC (EMILIA trial).
Brentuximab vedotin: CD30 Ab and a mitotic
inhibitor. Good response rates in refractory HL and
ALCL.
Immunotherapy
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First IL-2 and Interferon.
Sipuleucel-T: First immunotherapy vaccine
approved for a cancer by FDA (2010). Combines
patient's dendritic cells + prostatic acid phosphatase
+ GM-CSF.
OS advantage of 4 mos in castrate resistant, low
volume, MPC. Little ORR.
Immunotherapy
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Dendritic cells recognize tumor antigens and present
to CTLs. CTLs interact with dendritic cells via
CTLA-4. This interaction inhibits a tumor response.
Ipilimimab blocks this interaction, allowing T cells
to recognize and destroy cancer cells.
Median survival10 months vs. 6 months in patients
with advanced melanoma.
CTLA-4 Inhibition
Immunotherapy
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PD-1 inhibitors: Blocks receptors on T cells, which
when normally activated inhibits ability to kill tumor
cell. Represents direct interaction between tumor
cell and T cell.
CARs: Chimeric Antigen Receptors allow
introduction of T cell receptors (via a retrovirus) that
are specific for certain antigens. Thus far, impressive
in refractory lymphomas.
The Future
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Average survival advantage is 2-4 months.
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Cancer rates increased over the last 100 years. Why?
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Preventative strategies are most important.
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The role of tobacco, alcohol, viral pathogens, and
diet.