1. One of the most
challenging cancers to
treat is also one of the rarest.
Adrenal cancer is a form of
cancer that develops from the adre-
nal glands, which are located above the
kidneys and are chiefly responsible for re-
leasing hormones in response to stress. Ad-
renocortical carcinoma (ACC), also called ad-
renal cortex cancer, is a cancer of the
adrenal cortex that occurs when
cancer cells form in the outer layer
(cortex) of the adrenal gland.ACC
impacts the body's secretion of
adrenal hormones and patients
are often diagnosed when they
seek medical attention due to
symptoms associated with excess
hormone production. These
symptoms can include
fluctuations in weight, fluid reten-
tion and rapid onset of diabetes.
Other patients experience severe
fatigue, pain or a feeling of full-
ness, which can be caused by
the size of a large adre-
nal tumor.
ATR-101 is a
novel, oral drug
candidate that has
shown selective effects on
cells derived from the adrenal
cortex in preclinical studies.
Adrenal cancer is one of the most deadly
types of cancer, with few treatment
options available. Standard thera-
py, which causes severe side ef-
fects, has been the same for
more than 40 years. About 500
people will be diagnosed with
adrenal cancer this year in the
United States and most will die
within five years. The disease is
often diagnosed at a late stage
and surgery is rarely an option.
Pre-clinical
studies are a key step in
the development of new disease treatments. A com-
pund will only be tested in patients once it has been shown to
be effective in an animal model that reliably reflects the human
disease.
Pre Clinical Studies
Mitochondria perform crucial cellular reactions, including the production of energy through the mitochondrial RC, the regulation of
cell death, calcium metabolism and the production of reactive oxygen species. The RC comprises four enzymatic complexes
(complexes I-IV) embedded in the inner mitochondrial membrane.Dysfunction of the mitochondrial RC is a key player in a va-
riety of human disorders, including primary mitochondrial diseases caused by mutations both in the mitochondrial and
nuclear DNA (, as well as in common conditions, such as aging , diabetes , cancer. In order to gain a better understand-
ing about the drug and its effects, we determined which specific complexes is ATR101 attacking.
Conditions for spectrophotometric assays of respiratory chain complexes :
Approach and Goal
Complex I: (CI, NADH:Ubiquinone
Oxidoreductase)
Effect of Rotenone in Complex I
activity
DMSO
ATR101
Rotenone
-0.005
-0.004
-0.003
-0.002
-0.001
0
Effects of ATR-101 in Complex I
Mean initial concentration Mean Final concentration Standard Deviation
DMSO -0.00423 0.000231 1.000231
ATR101 -0.00393 0.000416 1.000416
Rotenone -0.00217 0.000473 1.000473
Drug Development for Rare CancersProject Sponsor: Dr. Tom Kerppola, Department of Biological Chemistry Project Supervisor: Dr. Yunhui Cheng. Student: Cristina Castillo
ATR-101
Adrenal gland cortex cells
Results :
Conclusion
After analyzing the data, a decrease in
slope is observed in Mitochondria(control)
activity.However, in order to clearly observe comple I activity
there must be a very drasctic slope secrease as shown in
the effect of rotenone in Complex activity I Figure. In our
experiment set up we tested ATR101 and DMSO change
in absorbance over time becauee ATR101 has been
dissolved in DMSO, therefore if there is any difference
in their absorbances it should represent actual ATR101
behavior. . Rotenone is a specific complex I inhibitor,
it blocks the electron transport chain (ETC) between NADH
dehydrogenase(Complex I) and CoenzymeQ. As expect, the
absorbance at 340 nm decreased slower in rotenone treated
group than vehicle treated group. The absorbance at 340 nm decreased
slightly slower in ATR101 treated group than in vehicle group,
but there were no significant difference between two groups.
The above results indicated that ATR101 dose not affect the activities
of Complex I.