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Brain Cancer

Pathways & Targets

AbbVie is exploring a vast array of pathways and proteins implicated in brain cancer cell growth and survival in order to identify possible therapeutic targets. Selected pathways and potential targets include, but are not limited to, the epidermal growth factor receptor (EGFR).

Mutated and Overexpressed EGFR

Amplification, rearrangements, and mutations of the epidermal growth factor receptor (EGFR) gene are the most common genetic alterations in glioblastoma (GBM), with amplification (and the subsequent overexpression of the EGFR protein) occurring in up to 50% of GBM tumors. 1,2

Glioblastoma (GBM)

GBM is a highly lethal and difficult-to-treat brain tumor with a median survival of only 3 months for untreated patients to 15 months following standard radiochemotherapy. The 5-year survival rate is approximately 5%. GBM is slightly more common in males, with a median age at diagnosis of 64 years.3-5

Mechanism of Disease

The cause of GBM is unknown. Exposure to ionizing irradiation has been associated with an increased risk of developing GBM, as have rare hereditary syndromes, ie, Cowden-, Turcot-, Lynch-, and Li-Fraumeni syndromes and neurofibromatosis type 1.6

Genetic and epigenetic changes contribute to the intratumor heterogeneity of GBM, and have detrimental effects on treatment resistance and residual disease. Significant genetic variance is observed between samples from the same tumor mass.7

Alterations affecting established signal transduction and tumor suppressor pathways have been identified.1 Amplification and subsequent overexpression of the receptor tyrosine kinases EGFR, PDGFRA, MET and FGFR, PIK3 and CDK4 are detected, as are deletions and mutations of PTEN, TP53 and CDKN2A/B.1

The most common genetic alterations in GBM are those of the EGFR gene, occurring in approximately 60% of tumors.2

EGFRvIII  is the most common mutation in GBM, producing a receptor with a truncated extracellular domain and ligand-independent constitutive activity.2,8 EGFRvIII   is detected almost exclusively in cases with EGFR amplification, resulting in tumors expressing both wild-type and mutated EGFRs.2

It has been suggested that EGFR amplification and EGFRvIII   mutation may correlate with poor prognosis, particularly in younger patients (<60 years of age).2,9

Diagnosis & Staging

Brain tumors usually are detected by computed tomography (CT) or magnetic resonance imaging (MRI) after patients present with symptoms, but the final diagnosis of type or grade is not made until after the tumor is surgically removed and pathologically examined.6,10 Symptoms include headaches, seizures, neurological deficits (ie, loss of vision, language or sensation), personality and behavioral changes, and memory loss.10

The World Health Organization (WHO) classifies gliomas according to their cell of origin (astrocytes or oligodendrocytes), and grades them from grade I–IV. Glioblastoma represents WHO grade IV.6

There are 2 types of GBM. Primary GBM (~90%) develop rapidly de novo without clinical or histologic evidence of a lower-grade glioma. Secondary glioblastomas progress from lower-grade gliomas, are most frequently found in younger patients, and carry a significantly better prognosis.11

Challenges in Treatment

Surgery for tumor debulking and obtaining tissue for evaluation, followed by chemotherapy and radiotherapy, is the current standard of care for newly diagnosed patients up to age 70 or fit elderly patients older than 70 years.6 Unfortunately, most patients will have a recurrence of GBM within 2 years of their original diagnosis.12,13

Available targeted agents affecting growth factor signaling pathways have demonstrated limited-to-no therapeutic efficacy.6

Unmet Need

In GBM, there is a need for treatments that provide improved response rates and additional survival benefits that will be meaningful for patients. Overall survival (OS) in newly diagnosed patients with GBM has remained relatively unchanged for 10 years, and patient prognosis remains poor.14

Glioblastoma has a high rate of recurrence, and median survival is less than 7 months in the recurrent setting.15 There are few treatment options to offer patients at disease recurrence. For recurrent GBM, reoperation may have only a modest benefit; in one study, median survival after reoperation was 36 weeks versus 23 weeks for patients who did not undergo reoperation.12

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address this unmet need.

EGFR

See how EGFR contributes to tumor proliferation.

Related Pathways & Targets

References

  1. Brennan CW, Verhaak RGW, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462-477.
  2. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280:5350-5370.
  3. Korshunov A, Sycheva R, Golanov A. The prognostic relevance of molecular alterations in glioblastomas for patients <50. Cancer. 2005;104(4):825-832.
  4. Bieńkowski M, Paskowski A, Stoczyńska-Fiedlu E, et al. Screening for EGFR amplifications with a novel method and their significance for the outcome of glioblastoma patients. PLoS One. 2013;8(6):e65444.
  5. Thakkar JP, Dolecek TA, Horbinski C, et al. Epidemiologic and molecular pathways prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014;23(10:1985-1996.
  6. Stupp R, Brada M, van den Bent MJ, et al. High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3):iii93-iii101.
  7. Ellis HP, Greenslade M, Powell B, et al. Current challenges in glioblastoma: intratumour heterogeneity, residual disease, and models to predict disease recurrence. Front Oncol. 2015;5:1-8.
  8. Zhao LI, Xu KI, Wang SW, et al. Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas. Histopathology. 2012;61:726-736.
  9. Shinojima N, Tada K, Shiraishi S, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003;63:6962-6970.
  10. Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and treatment of adult glioblastoma. Ann Transl Med. 2015;3(9):121.
  11. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2012;19(4):764-772.
  12. Barker FG, Chang SM, Gutin PH, Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery. 1998;42(4):709-720.
  13. Weller M, Cloughesy, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma - are we there yet? Neuro Oncol. 2013;15(1):4-27.
  14. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2012. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015.
  15. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17(8):2572-2758.