What Causes Brain Tumors??

– What is a Brain Tumor??

• Steven Brem, M.D.• Moffitt Cancer Center• January 23, 2009• West Palm Beach, FL

Basic Principles of Tumor Growth

What is the Cause of a Brain Tumor? “Where facts are few, speculation flourishes”

• Most common cause of a brain tumor, is metastatic lung cancer, so stop smoking

• Metastatic melanoma to the brain is the third most common metastases, and is linked to environment (sun exposure), and is, in part, preventable

• The cause of gliomas is unknown– 4% are clearly hereditary, 96% are “sporadic”

What is the Cause of a Brain Tumor? “Where facts are few, speculation flourishes”

1. Genetic – Altered genome – cancer genome- Microarray Glioma Microarray NIH Study (Dr. H. Fine) – REMBRANDT Data Base

– Personalized medicine

– Pharmacogenomics

– Total Cancer Care

2. Dietary– 30% of cancers, in general, linked to diet

– Obesity promotes tumor growth

– Little is known about brain tumors

– Carcinogens or additives in diet???

What is the Cause of a Brain Tumor?

3. VIRUS– HPV linked to cervical cancer and Vaccine effective– Epstein-Barr Virus linked to PCNS Lymphoma– Viral particles found in human b.t. specimens, but also found in

“normal” brain and many tumors without viral particles

4. HORMONES– Meningiomas – 3: 1 in females

– Incidence higher with Hormone Replacement Therapy

– Tumors increase with pregnancy

– Estrogen receptors targets for RU 486

– But other tumors, male slightly higher preponderance

– Overall, brain tumors are equal opportunity employers.

What is the Cause of a Brain Tumor?

5. Pesticides - Petrochemicals– Cluster of cases near factories, chemical waste dumps, and in

petroleum factory workers– Carcinogenic in animals

6. Ionizing RadiationIsraeli immigrant children treated with scalp RT for fungus developed

gliomas, meningiomas

Gliomas have developed years later at radiation-sites for other tumors

Laboratory models support ionizing radiation which causes misrepair of DNA, and damage to DNA

?? CT Scans – 2% of cancer incidence??????

What is the Cause of a Brain Tumor?

7.Cell Phones– Electromagnetic fields can induce mutations and DNA

damage in cell cultures

– Reports of higher incidence of brain tumors and leukemia in children living near high energy towers and lines

– Epidemiological data to support this hypothesis is not conclusive and the preponderance of data currently is that cell phones do not contribute to brain cancer burden

What is a Brain Tumor?- 3 Definitions• Large collection of abnormal cells residing in or near the

brain that has potential for proliferation, invasion, angiogenesis, cerebral edema, and by mass effect can cause neurological morbidity or even, at times, death, with growth determined by a series of mutations in the genes controlling cancer (oncogenes), modulated by local microenvironment, growth, molecular signature, and therapeutic options, such as surgery, chemotherapy, radiation therapy

• A mass of abnormal cells located in the head – on the surface, in the brain, or a tumor migrating to the brain.

• Nothing – if asymptomatic, benign, small, stable, cystic- Harvey Cushing story

What is a Brain Tumor?

• The World Health Organization (WHO) recognizes 120+ different types of brain tumors

• 3 Basic types (N. Vick):

– Tumors of the Brain – Gliomas –

– Tumors to the Brain – Metastases

– Tumors on the Brain – Meningiomas, Pituitary Tumors, Acoustic Neuromas, etc.

What is the Cause of a Brain Tumor?

• At a molecular - biological level, either

– Overdrive - Overamplification of Genes, RNA, Proteins that promote cell growth (EGFR, VEGF, cyclins, pAKT, ras, src, myc) or

– Loss of “brakes” (natural inhibitors) such as p53, p21, p16, thrombospondin,

– Probably not one single event, but a series of abnormal gene mutations

What is the Cause of a Brain Tumor?

• At a cellular level, either

– Cells of origin (Glial, Meningeal, Cancer) receive signal to proliferate

– Coordinated cellular “orchestra” with numerous cell types interacting – stem cells, blood vessel cells, immune cells, as well as astrocytes and nerve cells

What is the Cause (of Confusion) Regarding a Brain Tumor?

• Prognosis depends on many factors – Hard to predict the individual course – as biology of tumors is not “linear”

– Kaplan-Meier “survival” curves are for large group of patients with a similar histological diagnosis

– Survival and Quality of Life are related to

Many Factors

Barriers to Successful Therapy

• Complete Surgical Removal (or surgical cure) limited by infiltration of tumor along blood vessels and white matter fiber tracts, crossing the midline with many gliomas, even 99% tumor removal leaves 10 X 107

• Infiltration of gliomas leads to very high local recurrence rate, yet local therapies are limited because of the isolated tumor cells at a distance from the center

• Blood-brain barrier limits penetration of large molecules to the tumor cell

• Stem Cells may hide in “vascular niche” and are relatively radioresistant and chemoresistant

Barriers to Successful Therapy

• Sensitivity of surrounding vessels and neurons to chemotherapy and radiation therapy – “chemo-brain”

• Heterogeneity of the tumors at the immunological, histological, genomic level – ‘moving target’

• Ability of the tumor to spread into different compartments, e.g. from the brain to the cerebrospinal fluid and spread via the CSF, “seeding”

Barriers to Successful Therapy

• Biochemical “redundancy” of molecular pathways so that combinations may be required as with treatment of HIV, tuberculosis, hypertension – “triple therapy”

• Hypoxia leads to chemoresistance and radioresistance

• Poor animal models – Can cure in mice, but not in humans

Factors that Determine Outcome• Growth rate of the Tumor – Ki-67

• Size

• Benign vs. Anaplastic vs. Malignant

• Location, Location, Location

• Operability – Solid vs. Diffuse, Focal vs. Multifocal, Deep vs. Surface

• Access to Sophisticated Care – Team Approach

• Experience/ Expertise of the Center

• Compliance of the Patient, and Adherence of the Team to Best Practices – Guidelines

• Clinical Trials

Parasaggital Meningioma Case Presentation

Parasaggital Meningioma Case Presentation

• 74 y.o. male, father of cardiologist

• 4 year hx of R foot drop, worse after spinal surgery

• New weakness of R arm

• Seizures

• MRI shows a L parasagittal mass

Parasaggital Meningioma Case Presentation

Parasaggital Meningioma Case Presentation

Recurrent Glioblastoma

Case Presentation

• 8 months PTA, craniotomy per ____

• Completed 2 of 4 cycles of CI-980

• Completed EBRT

• Progressed through procarbazine (Sugen 101 protocol)

Surgery

Radiation Therapy

Chemotherapy

Recurrent Glioblastoma

Daumas-Dupport / Kelly Type II Growth Pattern (Solid +Infiltrative)

Recurrent Glioblastoma

The invasive radiations of a tumor prevent surgical cure

Recurrent Glioblastoma

Tumors are wrapped around blood vessels

Recurrent Glioblastoma

Oh, Those Vessels!!

Recurrent Glioblastoma

Edema!!

Recurrent Glioblastoma

What is OperableOperable?• Anterior R temporal lobe w mass effect

• “Bulky” central part of tumor-

not prominent in this case

Recurrent GlioblastomaWhat is InoperableInoperable?

• Infiltrative Tumor into Insula, Sylvian Vessels, Pia-Arachnoid• Vascular Network• “Edema” with Microscopic Disease

Tribute to Sheryl Shetsky

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