Advances in Oncology

Justin M. Markow, DOCoastal 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

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

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

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

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

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

t(9;22) results in a fusion product of ABL1 and BCR proteins.

Constitutively active TK, which ddrives cellular proliferation.

95% of CML cases Five year survival was 30%. Most patients progressed to blast phase/AML.

CML

The only cure is an Allogeneic Transplant. Infections, GVHD, thrombosis, rejection/relapse.

FDA approved Imatinib in 2001. TKI of the BCR-ABL protein.

A model for future cancer drug development. Five year survival rates are now 89%-95%.

CML

Not a “cure” in technical sense of the word. BCR-ABL is the pathogenic step. Clone is “addicted” to oncogene. Not the case with most malignancies. Few diseases have a single integral pathogenic

lesion.

Oncogenesis

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

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

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

Afatinib: Irreversible TKI. PFS and RR in LUX-Lung 3 trial.

Crizotinib: Inhibitor of ALK fusion protein. 4% of NSCLCs have translocation between EML4 and ALK. ORR 60%.

Small Molecule Inhibitors

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

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

Jak

JAK Inhibition

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

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

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

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

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

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

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

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

Average survival advantage is 2-4 months. Cancer rates increased over the last 100 years. Why? Preventative strategies are most important. The role of tobacco, alcohol, viral pathogens, and

diet.