Report on the Canadian Conference on Ovarian Cancer Research May 27-30, 2012
These are exciting times in ovarian cancer research. We just attended the Canadian Conference on
Ovarian Cancer Research (CCOCR http://www.ccocr.org/) in Quebec City, Quebec, Canada and the theme
of the conference was “Where there is a molecular path, there is a way.” Surprisingly there were only three or four
presentations which utilized animal models, the rest of the conference
including oral, poster and plenary talks were based on clinical research. The further analysis of ovarian cancer
subtypes and defining each of the subtypes by their genomic signatures,
phenotypic and morphological features,
and anatomical location to give insight into the potential site from which the
cancers originate, but more importantly, to devise effective “personalized”
therapies. It now appears that ovarian
cancer may be described as possibly 8 distinct cancers. Impressive technology is being brought to
bear on this disease. The use of
next-generation, massively parallel deep sequencing of the tumors brings new
insight into the complex changes underlying the cancers. Instead of considering the cancers from the
viewpoint of single gene mutations, it is clear that pathways instead of
individual genes need to be targeted.
Combined targeted therapies are bringing improved patient outcomes—but these
are often marginal gains. Increasing progression
free survival by 3 months is still considered a major therapeutic advance. Beyond gene signatures, investigations reveal
alteration in copy number of certain genes and specific chromosomal
rearrangements. Certain of these cancer
subtypes feature considerable genomic instability, especially the biggest
killer of them all, “high grade serous” cancer—of which more than 70% of
ovarian cancer victims succumb.
Yet lacking from these enlightened discussions and
state-of-the art technological advances is an increase in our understanding of
the underlying cause of ovarian cancer.
While it appears that the fimbriae of the Fallopian tube is the origin
of high grade serous cancers which are proposed to spread from tube to ovary to
the peritoneum, it remains an open question—what event caused the neoplastic
transformation in the first place? The
so called incessant ovulation hypothesis, proposed in 1971 by Fathalla is no
longer favored by the gynecologic oncologists, largely because of the postulate
that the ovarian surface epithelium the OSE is the origin of the disease. This idea is challenged the evidence that
serous disease my arise from the tubal epithelium, and also the emerging idea
that other forms of the disease may arise from endometriosis associated
lesions. The gifted gynecologic surgeons
who are “debulking” these cancers observe the similarity in appearance and
presentation of the endometrioid cancer with the endometriomas and propose a
causal relationship. The molecular
signature of the endometrial cancers and the endometrioid ovarian tumors
supports the clonal origins of the disease and help the physicians devise
targeted combinatorial therapies for the afflicted women.
We still favor the basic postulate set forth in the
incessant ovulation hypothesis—that ovulation is an inflammatory event and the
associated oxidative stress and inflammation is the molecular insult that
initiates the transformation. The
endometriosis origin when examined carefully also supports inflammation as the
prime driver of the disease—moreover, only endometriomas are associated with
endometrioid type of ovarian cancer, and these are endometriosis lesions on the
ovary itself—so called “chocolate cysts.”
The fimbriae is in close physical proximity to the surface of the ovary
and the insult associated with ovulation exposes the tubal epithelium to the
same inflammatory milieu as the OSE.
Tubal, endometriotic or ovarian surface—the inflammatory insult is the
common culprit.
Chemoresistance, recurring disease, poor prognosis—all the
unfortunate hallmarks of ovarian cancer.
Molecular medicine advances the therapeutic options and outcomes are
improving. Yet there is no better cure
for the disease than prevention. And
here is probably the single most important feature of the chicken model of
ovarian cancer—it provides the opportunity to devise effective interventions that
are potentially able to prevent the disease in the first place. Furthermore, the hens provide us with a tool
to look at the very first initiating events.
What prevents ovarian cancer?
Reducing the number of life time ovulations is the best intervention
thus far described. Parity, breast
feeding, steroidal contraceptives—all lead to significant reductions in cancer
incidence. Reducing the inflammation associated
with ovulation maybe another effective preventative. Also reducing the inflammation associated
with endometriosis is also likely to have important effects on ovarian cancer
reduction. And we propose that dietary
intervention with natural foods rich in antioxidants with anti-inflammatory
properties will provide the population with a significant reduction in ovarian
cancers when adopted. This hypothesis
has substantial support from dietary intervention studies in hens, and provides
the foundation for clinical trials in women.
