335multiply uncontrollably, causing B cell lymphomas. A gene called BCL6 codes for
a protein, which is a transcriptional repressor, i.e. it can shut off the functioning of
genes in B cells and other cells of the immune system and prevent them from being
expressed. The BCL6 protein is normally produced only during a specifi c stage of
B cell development and is never made again. But deregulation of BCL6 can cause
the protein to be produced when it should not be. The unwelcome presence of the
BCL6 protein blocks the expression of important genes that normally protect cells
from becoming cancerous. A peptide called BPI has shown promise in treating
B-cell lymphomas by specifi cally blocking the cancer-causing effects of the BCL6
protein. However, until now, there has been no way to distinguish between diffuse
large B cell lymphomas that are caused by BCL6 deregulation and those cases in
which BCL6 is expressed but does not actually drive the cancer. In an effort to iden-
tify cases of lymphoma that are uniquely susceptible to BPI inhibitor therapy,
genomic array ChIP-on-chip was used to identify the cohort of direct BCL6 target
genes (Polo et al. 2007 ). In primary diffuse large B cell lymphomas classifi ed on the
basis of gene expression profi les, these BCL6 target genes were clearly differen-
tially regulated in BCR tumors, a subset of DLBCLs with increased BCL6 expres-
sion and more frequent BCL6 translocations. Only BCR tumors were highly
sensitive to the BCL6 peptide inhibitor, BPI. This genetic signature can help physi-
cians to enroll patients in clinical trials of the new targeted therapy who are most
likely to benefi t from it. Patients who do not fi t this genetic profi le will be spared a
drug treatment that would be ineffective.
A combination of targeted sequencing and microarray analyses in non-Hodgkin
lymphoma cell lines was used in a study to fi nd mutation and gene expression
patterns linked to resistance or sensitivity to dacetuzumab, a CD40-stimulating anti-
body being investigated for the treatment of diffuse large B cell lymphomas and
other B cell cancers (Burington et al. 2011 ). The results showed that a gene expres-
sion signature associated with activation of the TNF CD40 pathway can help predict
response to a new B cell cancer treatment targeting the pathway. A qRT-PCR assay,
which assesses the expression of 15 genes, was subsequently used to predict dacetu-
zumab treatment response in cell lines, mouse xenograft models, and clinical sam-
ples. Generally, cell lines harboring mutations in the tumor suppressor gene p53
were more likely to respond to the CD40 stimulation treatment, as were cell lines
with widespread DNA damage or unusually high proliferation rates. Elevated levels
of the transcriptional repressor proto-oncogene BCL6 also coincided with treatment
sensitivity. In contrast, cell lines exhibiting expression patterns consistent with
CD40 pathway activation prior to treatment tended to be resistant. In clinical sam-
ples from diffuse large B cell lymphoma patients treated with dacetuzumab during
phase I/II trials of the therapy, the response signature accurately predicted treatment
response − specifi cally, tumor shrinkage − for 80 % of the cases. Patients classifi ed
as having treatment sensitive tumors based on the expression signature also had
signifi cantly longer progression-free survival times following dacetuzumab treat-
ment than those with tumors classifi ed as treatment resistant.
Personalized Management of Cancers of Various Organs