Molecular Biology of Head and Neck Cancer

Joseph Califano, M.D.

Eliminating Surgery, Chemotherapy

and Radiation: New Therapy for Head and Neck Cancer


Department of Otolaryngology-Head and Neck Surgery

Johns Hopkins Medical SchoolBaltimore, MD USA

Milton J Dance Head and Neck CenterGreater Baltimore Head and Neck Center

Baltimore, MD USA


Why I have enough Cialis for a small town in Florida in my office

drawer





Baltimore, MD USA


No Relevant Financial Relationships with Commercial Interests


I am pro America

Primary Treatment for HNSCC

• Surgery• Radiation• Surgery + Radiation• Radiation + Chemo• Surgery + Radiation + Chemo

A surgeon’s guide to why radiation (and chemotherapy) works

A surgeon’s guide to why radiation (and chemotherapy) works

• Implies that tissue damage is inevitable with inevitable with cytotoxic therapy

• Separation of curves is the goal of innovation

Primary Treatment for HNSCCRadiation and Cytotoxic chemotherapy – the “healing rays” can cause

• xerostomia, fibrosis• affect taste• affect taste• Dysphagia • Cytotoxic (cell killing) chemotherapy

– Chemo• Magnifies adverse effects or radiotherapy• Life threatening complications rare but significant


• Surgery –”You are going to cut out my what?” can cause– Dysphagia– Dysphagia– Dysarthria, dysphonia, aphonia– Poor Cosmesis– Shoulder dysfunction


• Are there other things to target specifically in cancer

Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

Jones et al. Science, 2008

• average of 63 genetic alterations/ tumor• Only looked at mutations and DNA copy alteration• (didn’t look at miRNA, epigenetics

The Molecular Revolution

• 1970’s interferon will cure cancer• Gleevec: small molecule inhibitor of abl tyrosine kinase domain for CMLtyrosine kinase domain for CML

The Molecular Revolution

EGFRpathway

EGFRpathway

Erbitux

• Humanized monoclonal Ab directed against EGFR, widely used

• Safety Profile:• Safety Profile:– 3% risk of hypersensitivity, <0.5% interstitial pneumonitis (2/3 with preexisting pulmonary fibrosis, one death)

– acneiform rash for most patients

• IV infusion

Kaplan-Meier Estimates of Locoregional Control among All Patients Randomly Assigned to Radiotherapy plus Cetuximab or Radiotherapy Alone

Bonner, J. et al. N Engl J Med 2006;354:567-578

Kaplan-Meier Estimates of Overall Survival among All Patients Randomly Assigned to Radiotherapy plus Cetuximab or Radiotherapy Alone

Bonner, J. et al. N Engl J Med 2006;354:567-578

Platinum-Based Chemotherapy plus Cetuximab in Head and

Neck CancerVermoken et al. NEJM, 2008

• Recurrent or Metastatic patients do patients do better with Cetuximab

Phase II Study of Cetuximab for High Risk Premalignant Disease

of the Head and Neck

Pretreatment: moderate-severe dysplasia

Posttreatment: no dysplasia

A Phase II Trial of Tadalafil in Patients with Squamous Cell Carcinoma of the for High Risk Premalignant Disease of the

Head and NeckJoseph Califano, M.D. and Ivan Borrello, M.D.




Baltimore, MD USA

Viagra and Cialis affect the immune system

Joseph Califano, M.D. and Ivan Borrello, M.D.Department of Otolaryngology-

Head and Neck Surgery Johns Hopkins Medical SchoolJohns Hopkins Medical School

Baltimore, MD USA


Baltimore, MD USA


I am not an immunologist



Immunologists

JC office

Where immunologists work

Immunologists go to lunch here



But I can see them But I can see them from my window

Tumor

Tumors can recruit different host cell populationsto avoid T cell recognition

TumorspecificCTL

MDSCs can mediate T-cell suppression through Arg-1 and Nos2 expression

Cytotoxic T cell response

Bronte Serafini et al: J Immunol. 2003 Jan 1;170(1):270-8.

response

Inhibitors of iNOS

cGMPPDE5

+

cyclaseGTP

Sildenafil

VasodilatationGMP

PKG

PDE5 inhibition: mechanism of action on MSCs

Tumor

L-arg

iNOS mRNA iNOShur

Arg1 ++

TumorspecificCTL

NO

O2-

ONOO-

Figure 3: PDE-5 inhibition exerts a measurable immune-mediated anti-tumor effect. Balb/c or Rag-/- mice werechallenged with CT26 s.c. and followed for tumor-free survival inthe presence or absence of sildenafil.

Modulation of HNSCC immune response via PDE5 inhibition

• A novel means of overcoming Tcell immune response to HNSCC

Viagra Reverses T-cell inhibition in HNSCC patients

Figure 5: PDE5 Inhibition Augments T cell Proliferation in HNSCC PBMCs. Peripheral blood from HNSCC or a healthy donor was stimulated with anti-CD3/CD28 beads in the presence or absence of Viagra for 5 days. Fold change was determined by expansion of CD4 or CD8 cells compared to baseline.

Specific Aim 2: To determine effect of phosphodiesterase 5 inhibition on in peripheral T cell function in patients with HNSCC.

Specific Aims of Study

HNSCC.Using T cell expansion assays with anti-CD3/CD28 magnetic beads, we will measure the stimulation index (T cell number post-expansion/T cell number at baseline) as a measure of T cell function.

Primary HNSCC (resectable or unresectable) without evidence of pre-existing immune suppression or contraindication to tadalafil and available for biopsy of tumor

Control group:

Randomization 5:3, 40 patients treated: control

Treatment group:

Schema

Control group: observation alone

Treatment group:Talalafil 10 mg. po QD X 14 D

day 14:Complete assessment, biopsy OR surgical resection. Peripheral blood sampling prior to biopsy or resectionStandard therapy (surgery, radiation, and/or chemotherapy)

Continued surveillance

Primary Endpoint and Statistics

Primary Statistical Analysis: A total of 40 patients will be randomized in this study, 25 to tadalafil and 15 to no treatment. The primary analysis will be an unpaired t-test of the changes between the two arms, comparing T-test of the changes between the two arms, comparing T-cell activation.This will provide 81% power for the statistical detection of a 0.8 SD difference in post-pre change between the two groups (two-sided alpha=0.10)

Other interesting novel trials and agents

• New EGFR antibodies• Antibodies directed against general tyrosine kinase domains affecting growth, angiogenesisangiogenesis

• EGFR tyrosine kinase inhibitors• HPV immune therapy trials• Other tyrosine kinase inhibitors for angiogenesis, growth, invasion pathways

• Blockade of sugar metabolism in tumors• Akt/mTOR pathway inhibitors

Other interesting strategies

• Selection of therapy based on molecular prognostic criteria: theragnosis

• Combining conventional and molecular • Combining conventional and molecular therapies

• Not yet able to avoid cytotoxic therapies– Psychologic barriers

Thank You

• Ivan Borrello• Zubair Khan

Documents

Molecular Biology of Head and Neck Cancer