California Cancer Research Program
Completed
Projects
The following Principal
Investigators have completed their research as funded by CRP. Where applicable,
publications resulting from CRP funding are also included.
CYCLE II FINAL LAY
ABSTRACTS
Investigator-Initiated
Awards
Jonathan
S. Berek, M.D.: Nutrient Gene Interactions
in Ovarian Cancer
Eric
J. Stanbridge, Ph.D.: Evaluation of MN/CA9
Protein Expression in ASCUS Pap Smears as a Diagnostic Biomarker of Cervical
Dysplasia/Neoplasia
Jeffrey
S. Weber, M.D., Ph.D.: HPV Heat Shock Protein
Vaccine for Cervical Dysplasia
Petra
E. Wilder-Smith, D.D.S., Ph.D.: Non-Invasive Diagnosis of
Pre-Malignancy and Malignancy
Rowan
T. Chlebowski, M.D., Ph.D.: Exercise and Androgen
Ablation in Prostate Cancer
Laura
E. Crocitto, M.D.: Screening Telomerase for
Prostate Cancer Detection
Richard
Essner, M.D.: Morphologic Changes to the
Sentinel Nodes in Melanoma: A Novel Mechanism for the Development and Treatment
of Metastases
Jean
Y.J. Wang, Ph.D.: Molecular Tools to Assess
the Efficacy of Cancer Therapy
Catherine
Ley, Ph.D.: HPV Infection and Cervical
Cancer Screening in Hispanics
Min-Ying
Lydia Su, Ph.D.: Selective Thrombosis of
Tumor Vessels for Cancer Therapy
Clinical Scientist
Development Award
James
L. Rubenstein, M.D., Ph.D.: Rituximab in the Treatment of Primary CNS
Lymphoma
Marc
A. Seltzer, M.D.: PET Imaging for Prostate
Cancer
Small
Business Collaboration Award
John
P. Fruehauf, M.D.: Biomarker Angiogenesis
Index Stratifies Metastatic Risk
Nutrient Gene Interactions
in Ovarian Cancer
Jonathan S. Berek, M.D.
University of California,
Los Angeles
$990,389.33 / 36
months
Ovarian
Cancer
Investigator-Initiated
Award
Ovarian cancer is a major
problem because there is no effective means of early detection and about
three-quarters of women have advanced stage disease when they are
diagnosed. Ovarian cancer is the
fifth leading cause of death in women in the United States, and has the highest
fatality to case ratio of all of the gynecologic malignancies, with nearly
24,000 cases and over 13,000 deaths expected in 2003. Although many of these
cancers are responsive to chemotherapy, only 20% of women with ovarian and
peritoneal cancers are alive and free of disease at five years. Therefore,
effective preventative strategies and other means of disease control are being
sought. There is evidence
that pregnancy, the oral contraceptive pill, and several nutrients may play a
role in the reduction of ovarian and peritoneal cancer risk. Although dietary factors have been
associated with the etiology of ovarian cancer, especially dietary intake of
retinoids, dairy and soy products, the relationship
between fat, fiber, and other nutritional factors and the clinical progression
of epithelial ovarian and peritoneal cancers as well as the molecular and
genetic alterations thought to be involved in this process are largely
unstudied.
The objectives of this study
were to evaluate the effects of nutrients on the progression of all stages of
ovarian and peritoneal cancer and to explore the interactions between nutrients
and the intrinsic host susceptibility in order to better understand nutritional
and molecular mechanisms for the progression of these cancers. Several public service announcements
were made on television, radio and the print media, especially local newspapers
covering West Los Angeles, South Los Angeles, and the San Fernando Valley
areas. Flyers and pamphlets
describing the study were distributed widely in the UCLA community, the Medical
Center and mailed to numerous cancer support groups.
Over 100 patients were fully
screened and identified as potential candidates for entry on to this
protocol. This screening process
netted 21 subjects who were randomized into the phase III study. Patients who
had been entered onto the trial were carefully monitored, and serial blood
samples were drawn and stored for analysis, as per the protocol. Toward the end of the second year of
funding, we were notified that we would not receive a thrid year of funding.
By the close of accrual to the study (7/15/02), 7 patients dropped out
because of progressive disease and/or too ill to return to follow-up. One additional patient dropped out
because she wanted to be in the intervention group. Thirteen subjects completed the full
follow-up and close-out visits through the end of the trial grant period
(7/1/02-10/31/02).
Blood samples are currently
being assayed for the parameters as outlined in the study, and we anticipate
that the full analysis will be published. Serum samples from 13 patients in
women undergoing dietary intervention was added to ovarian cancer cell lines in
vitro in another series of experiments. This same procedure has been used to
screen a wide variety of cell lines in vitro to assess potential growth
differences caused by the use of serum from the same patient before and after
the commencement of a diet very low in fat, high in fiber and supplemented with
soy protein and extra fruits and vegetable. The results of these experiments are
pending. The study demonstrated the extraordinary difficulty in accruing
patients to a randomized trial of dietary intervention in women with ovarian and
peritoneal cancer, with a ratio of potentially eligible and interviewed patients
to accrued and enrolled patients of about 20%. The most common reason for non-accrual
was the patient refusal because of the randomization, inaccessibility secondary
to geographic considerations, and a very low-fat intake
diet.
Exercise and Androgen
Ablation in Prostate Cancer
Rowan T. Chlebowski, M.D., Ph.D.
Harbor-UCLA Research &
Education Institute
$186,488.00 / 24
months
Prostate
Cancer
Pilot and Feasibility Study
Award
An
increasing number of studies have suggested an inverse association of physical
activity on prostate cancer. In
addition, androgen ablation, a mainstay of prostate cancer patient management
had been implicated as potentially mediating life threatening conditions
including osteoporosis fractures, coronary heart disease and diabetes. Since in other populations physical
activity has been associated with decreased diabetic complications and
improvement in coronary heart disease risk factors we hypothesize that a
supervised exercise program could be beneficial in prostate cancer patients by
mitigating co-morbid conditions and directly influencing prostate cancer.
To assess the feasibility of
evaluating the hypothesis that exercise could successfully reduce co-morbidities
expected with androgen ablation a pilot study involving patients with diagnosed
prostate cancer without widespread metastases was conducted. Ten patients (five with androgen
ablative therapy and five without androgen ablation) were randomized in an
exercise group and ten patients (four with androgen ablative therapy and six
without androgen ablation) in a control group not offered an exercise
program. Baseline assessment
identified individuals without androgen ablation as having normal testosterone
levels compared to the extremely low testosterone levels seen in those with
androgen ablation. The exercise
program involved thirty minutes of supervised exercise three times per week
under the direction of an exercise physiologist performed at the clinic
site. At baseline, lipid profile,
blood pressure, body composition, glucose tolerance and insulin levels, PSA, and
muscle strength were evaluated.
These parameters were scheduled to be reevaluated after completion of the
rigorous exercise program. All
participants randomized to the no-exercise program returned for their second
evaluation visit. Unfortunately,
60% of the participants randomized to the exercise program failed to complete
their program. Most withdrew after
experiencing a limited number of sessions precluding any definitive
determination of the effects of a program pf rigorous exercise on study
parameters. Attempts at further
recruitment identified resistance in the participant burden involved in the
exercise program (travel to the exercise facility and the physical effort
required). We conclude that a
rigorous supervised exercise program performed at a central location may not be
feasible for a population of elderly prostate cancer patients recruited from the
general population. If the exercise
hypothesis is to be tested a more moderate program of exercise perhaps
implemented in the local community setting or a more rigorous evaluation of
potential participant’s interest in completing such a program (perhaps by use of
a run-in) will be required.
Screening Telomerase for
Prostate Cancer Detection
Laura E. Crocitto, M.D.
City of Hope National
Medical Center
$213,750.00 / 24
months
Prostate
Cancer
Pilot and Feasibility Study
Award
Prostate Cancer is a leading
cause of death in American males today. Screening for prostate cancer has been
hotly debated from a cost-benefit standpoint. The current method for screening
involves the use of physical exam and serum Prostate Specific Antigen (PSA)
measurement. Both of these modalities are insensitive and lack the specificity
for the optimal detection of early stage prostate cancer. The identification of
new markers for the detection of this disease is greatly
needed.
One candidate marker, which
has recently been identified, is the human telomerase enzyme and its various
components. Telomeres are structures found on the ends of human chromosomes.
Chromosomes are those structures inside our cells, which contain genetic
information. Telomeres are necessary for cells to divide normally. Part of the
telomere is lost each time the cell divides until eventually the telomere is so
short that it can no longer function properly. At this point the cell dies.
Cancer cells have found a way to prevent loss of the telomeres. They produce an
enzyme (protein) which is called telomerase. This enzyme allows cancer cells to
continue to divide unchecked.
Telomerase activity has been
identified in approximately 90% of prostate cancers. Recently, telomerase
activity was also found to be present in the Expressed Prostatic Secretions (EPS) of patients with prostate cancer.
In addition, high levels of expression of the components of the telomerase
enzyme complex can serve as a marker of telomerase activity and thus, tumor
detection. Our pilot project is aimed at identifying the most sensitive and
specific methods for detecting telomerase activity and its components in the EPS
of men undergoing evaluation for the diagnosis of prostate cancer. Since the
pilot study began, we have established a method for EPS collection, and
evaluated 30 EPS samples. In patients with prostate cancer, hTR detected 2/12 for a sensitivity of 16% and specificity
of 93%. hTERT detected 6/6
prostate tumors for a sensitivity of 100% and specificity of 57% and TRAP
detected 0/5 prostate tumors.
The detection of hTERT by RT-PCR appears to be a promising new method for the
detection of prostate cancer in EPS.
1.
Crocitto LE, Korns D,
Kretzner L, Shevchuk T,
Blair SL, Wilson TG, Ramin SA, Kawachi MH, Smith SS. Prostate cancer molecular markers
GSTP1 and hTERT in expressed prostatic secretions as predictors of biopsy results.
Urology. 2004 Oct;64(4):821-5.
2.
Fuller RA,
Clark J, Kretzner L, Korns
D, Blair SL, Crocitto LE, Smith SS. Use of microfluidics chips for the detection of human telomerase
RNA. Anal Biochem. 2003 Feb 15;313(2):331-4.
Richard Essner, M.D.
John Wayne Cancer
Institute
$269,040.00 / 24
months
Skin
Cancer
Pilot and Feasibility Study
Award
Malignant melanoma once
considered a rare disease now represents 4% of all cancers in the
In the early 1990s
investigators at the John Wayne Cancer Institute (Santa Monica) devised an
alternative approach to the management of the regional lymph nodes in
melanoma.
Intraoperative lymphatic mapping and
sentinel lymphadenectomy (LM/SL) was devised as a
minimally invasive alternative to the traditional approaches to the regional
lymph nodes. LM/SL was based on the
observations that lymphatic vessels leading from the skin to the regional lymph
nodes can be mapped and the first lymph nodes (sentinel node, SN) could be
identified and separated from the adjacent secondary (non-sentinel, non-SN)
lymph nodes. This procedure allows
surgeons to determine the presence or absence of melanoma cells in SN without
performing a complete lymph node dissection to discover cancer
deposits.
In the past ten years
considerable scientific effort has focused on the immunology of cancer and in
particular on the creation of immune based therapies for melanoma. The rationale for immunotherapy is based
on understanding of the interaction of melanoma and the inherent immune function
of the individual. With increasing
understanding of the immune system scientists have discovered a population of
white blood cells critical for recognition and response to cancer. Dendritic
cells are the most potent of the antigen presenting cells yet represent only a
very small fraction of the white blood cell population. Dendritic
cells are found throughout the blood stream, lymph nodes, and skin.
Our investigations are a
result of the unique opportunity that has arisen from the development of
LM/SL. We have found that both the
physical appearance and function of dendritic cells in
SN are altered in patients with melanoma, and this is related to the growth and
increasing patient age. We continue
to investigate these changes to SN and methods to reverse the immune
dysfunction. We suspect these
findings may be relevant to both the growth of the original skin cancer, but
potentially also the pattern of spread of melanoma from the skin to lymph nodes
and other sites.
1.
Essner R, Lee JH, Wanek
LA, Itakura H, Morton DL. Contemporary surgical
treatment of advanced-stage melanoma. Arch Surg. 2004
Sep;139(9):961-6; discussion 966-7.
2.
Essner R, Chung MH, Bleicher R, Hsueh E, Wanek L, Morton DL. Prognostic implications of thick
(>or=4-mm) melanoma in the era of intraoperative
lymphatic mapping and sentinel lymphadenectomy. Ann
Surg Oncol. 2002 Oct;9(8):754-61.
3.
Essner R and Cochran AJ. Sentinel node biopsy: not
only a staging tool? Recent Results Cancer Res. 2002. 160: p.
133-48.
4.
Essner R, Kojima M. Dendritic cell function in sentinel nodes. Oncology (Huntingt). 2002 Jan;16(1 Suppl 1):27-31.
5.
Essner R,
Kojima M. Surgical and molecular approaches to the sentinel lymph
nodes. Ann Surg Oncol. 2001
Oct;8(9 Suppl):31S-34S.
Biomarker Angiogenesis Index
Stratifies Metastatic
Risk
John P. Fruehauf, M.D.,
Ph.D.
Oncotech,
Inc.
$94,887.82 / 12
months
Prostate
Cancer
Small Business Collaboration
Award - Phase I
Prostate cancer is the
leading cause of cancer in men, and the second leading cause of cancer death for
men. However, many men may be found
to have prostate cancer at an early stage when it is still confined to the
prostate, making it possible to potentially cure these men by surgical removal
of the prostate and tumor. What is not clear is how to identify those men with
disease apparently confined to the prostate who have
actually had undetectable microscopic spread of the cancer out of the prostate.
Cancer cells can escape the prostate in three ways. They can grow through the prostate
capsule into adjacent structures, which can be identified by the
pathologist. However, if the cells
escape through the lymph system circulation, or through the blood stream, this
cannot be detected by routine pathology tests. One way to determine if prostate
cancer has spread is to perform bone scans and CT scans to identify sites of
metastasis. Unfortunately, these
techniques are not sensitive enough to accurately identify patients with very
small, but clinically significant, numbers of cells that have escaped. For men
who have undergone “curative” radical prostatectomy, within 10 years
approximately 10% of these men will have died of metastatic prostate cancer that was undetected
initially. These patients
might benefit from a better method of predicting if cells have escaped. Such a method would help the physician
caring for these patients to offer additional therapy, such as hormone therapy,
immediately after surgery rather than waiting until after the disease has
recurred. On the other hand, men
who have a low risk of cancer spread could safely avoid therapy, and so avoid
the associated side effects. Our study was directed toward the validation of a
biomarker profile that can distinguish between aggressive carcinomas of the
prostate that are likely to have spread versus those that are unlikely to have
spread. The biomarker profile is based on the pivotal roles of tissue invasion
and an increased number of small blood vessels that grow into more aggressive
prostate cancers. Our group has developed an innovative numerical scale of
molecular and pathological events called the angiogenesis index (AI) that
appears to be significantly associated with prediction of progression of
prostate cancer from a non-invasive state into an aggressive carcinoma that is
likely to have spread even though on gross examination by the pathologist the
tumor appears to be confined to the prostate. This index of early detection
should accurately stratify patients with prostate carcinoma into low versus high
metastatic risk groups. In our training sets, both
invasion beyond the prostate to the seminal vesicles and the angiogenesis index
were significantly associated with an increased relative risk of death after
adjustment for tumor stage and grade. We have validated our methods and
correlated our IHC procedures with outcomes for 100 cases of primary prostate
carcinoma divided between low and high-grade tumors. Rigorous controls were
employed to ensure that biomarker tissue measurements were highly reproducible
and accurate. The study we performed that was funded by the CRP helped us to
further validate the angiogenesis index so that it can be offered as a routine
clinical test to prostate cancer patients. Urologists are now utilizing these
biomarkers to help them improve their detection of aggressive disease and
stratify patients for more appropriate treatment planning. We believe that this newly validated
testing can help doctors spare patients who have low risk disease from taking
unnecessary therapy, while increasing the odds that patients with more
aggressive prostate cancer will aggressive therapy. In this way
the angiogenesis index that was developed in part through the support provided
by this grant can allow the treating physician to tailor therapy to the
individual patient's unique tumor biology.
HPV Infection and Cervical
Cancer Screening in Hispanics
Catherine Ley, Ph.D.
Stanford
University
$296,789.00 / 36
months
Cervical
Cancer
New Investigator Award
No final report
submitted.
Rituximab in the Treatment of Primary
CNS Lymphoma
James L. Rubenstein, M.D.,
Ph.D.
University of California,
San Francisco
$306,279.96 / 36
months
CNS
Lymphoma
Clinical Scientist
Development Award
No final report
submitted.
1.
Rubenstein, J.L, Fischbein, N., Aldape, K., Burton,
E., and Shuman, M. Hemorrhage and VEGF Expression in a Case of Primary Central
Nervous System Lymphoma: Role of Vascular Endothelial Growth Factor. J. Neuro-Oncology 2002. 58(1) 53-56.
2.
Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott
M, Damon L, Ignoffo R, Aldape K, Shen A, Lee D, Grillo-Lopez A, and Shuman MA.
Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment.
Blood. 2003. 101(2): p. 466-468.
Book
Chapters
1.
Pathophysiology of Disease: An Introduction to Clinical Medicine, 4th ed. Neoplasia. Tripathy, D and Rubenstein,
J.L. [edited by] Stephen J. McPhee,
Vishwanath R. Lingappa, William F. Ganong. New York :
Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2003. 760
pp
2. Brain Metastases from
Genito-Urinary Cancer: Germ Cell, Testicular, Prostate and Bladder Cancer Theodosopoulos, P., Rubenstein, J. and
McDermott in Brain Tumors Spetzler, R..
In Press.
PET Imaging for Prostate
Cancer
Marc A. Seltzer,
M.D.
University of California,
Los Angeles
$307,326.40 / 36
months
Prostate
Cancer
Clinical Scientist
Development Award
Positron
emission tomography (PET) is a non-invasive whole body imaging test that
produces images that show body function, such as glucose metabolism of
tumors. Using this technique
together with a positron emitting radioactive tracer, one can image tumor
metabolism in patients with cancer. Two radioactive tracers of metabolism that
can be imaged with PET are [F-18] fluorodeoxyglucose (FDG) which is a marker of
glucose metabolism and C-11 acetate which is an intermediary probe of cellular
lipid metabolism. Both tracers have shown promise in preliminary studies in
prostate cancer. The purpose of
this project was to evaluate the performance of PET metabolic imaging for
determining the presence and extent of disease in patients with prostate
cancer. Our study population
comprised patients with newly diagnosed prostate cancer as well as patients with
recurrent cancer suspected by a rising serum PSA level following local treatment
such as radical prostatectomy or radiation therapy. The ability of PET to more accurately
determine the extent of disease could potentially result in more appropriate
treatment strategies for the majority of prostate cancer
patients.
During the
past three years, we have achieved a better understanding of the role of PET
imaging using C-11 acetate and FDG-PET in the diagnosis and staging of
prostate. We performed C-11 acetate
and FDG-PET scans in patients with locally advanced primary prostate cancer and
compared the imaging results from cancer patients to those obtained in a group
of healthy normal volunteers. We
found that both FDG and C-11 acetate PET scans were unable to reliably
differentiate benign from malignant prostate tissue. We concluded that neither FDG nor
C-11 acetate could be used for determining the presence and extent of tumor
within the prostate gland.
We did,
however, observe that both FDG and C-11 acetate PET can be succesfully used as a
problem solving tool to determine the presence and extent of distant sites of
prostate cancer spread (metastases) in patients who have failed prior local
therapy with radical prostatectomy or radiation therapy. Combined PET imaging using both FDG and
C-11 acetate demonstrated evidence of metastatic disease in over 40% of patients
with suspected tumor recurrence based on a high level of serum PSA or a rapid
rate of rise in the level of the serum PSA. In a significant number of
patients, PET scans detected unsuspected sites of metastases that were either
not seen or were poorly visualized by conventional imaging tests such as bone
scan and computed tomography. In a
direct comparison of C-11 acetate PET to FDG-PET, C-11 acetate appeared to be a
more sensitive and specific test than FDG-PET. Our relatively small patient
sample size did not allow us to make a definitive conclusion as to whether C-11
acetate PET is a more reliable test than FDG-PET for detecting prostate cancer
metastases.
We used PET
scanning to quantify the metabolic activity of prostate malignancies and found
that some tumors prefer C-11 acetate over FDG as a fuel for their
metabolism. This confirmed the
results of prior in-vitro studies demonstrating that some neoplasms prefer the
lipid metabolic pathway over the glucose metabolic pathway. Interestingly, in a subset of patients
with advanced metastatic prostate cancer that was unresponsive to systemic
hormonal therapy, we found a majority of tumors appeared to have a higher rate
of glucose utilization (as measured by FDG-PET) compared to lipid metabolism (as
measured by C-11 acetate PET).
1.
Seltzer MA,
Strum SB, Scholz, MC, Belldegrun A, Satyamurthy N, Bobinski KP, Phelps ME, Czernin
J. Comparison of whole body 11C
Acetate and FDG PET in patients with prostate cancer. Journal of Nuclear Medicine 2000;
41:142P.
2.
Seltzer MA,
Sparks R, Stout DB, Satyamurthy N, Dahlbom M, Phelps ME, Barrio JR. Radiation Dose Estimates for 11C-Acetate
Whole Body PET Imaging. Journal of
Nuclear Medicine 2001;
42:242P
3.
Seltzer MA, Jahan
SA, Dahlbom M, Stout, DB, Satyamurthy N, Phelps ME, Barrio, JR, Czernin, J.
11C- Acetate PET Imaging of primary and recurrent prostate cancer: comparison to normal
controls. Journal of Nuclear
Medicine 2002;
43:117P
4.
Seltzer MA,
Jahan SA, Dahlbom M, Satyamurthy N, Barrio JR, Phelps ME, Czernin J.
Combined metabolic imaging using C-11 acetate and FDG PET for the
evaluation of patients with suspected recurrent prostate cancer. Journal of
Nuclear Medicine
2003; 44(5 Supplement):132P.
5.
Seltzer M A, Jahan
SA, Sparks R, Stout DB, Satyamurthy N, Dahlbom M, Phelps ME, Barrio JR. Human radiation dose
estimates for C-11 acetate whole body PET.
Journal of Nuclear Medicine 2003; 44(5 Supplement):102P.
Evaluation of MN/CA9 Protein
Expression in ASCUS Pap Smears as a Diagnostic Biomarker of Cervical
Dysplasia/Neoplasia
Eric J. Stanbridge, Ph.D.
University of California,
Irvine
$745,873.00 / 36
months
Cervical
Cancer
Investigator-Initiated
Award
Approximately 10% of all Pap
smears are diagnosed as ASCUS. Up
to one third of patients receiving a Pap smear diagnosis of ASCUS will harbor a
significant lesion, termed squamous intraepithelial
lesion (SIL), and more rarely a carcinoma.
The major objective of this
study is to provide an adjunct test to the conventional Papanicolaou (Pap) smear, that will allow for identification
of those patients with a diagnosis of ASCUS who harbor a significant lesion (SIL
and/or carcinoma).
We have identified a novel
biomarker, the MN/CAIX protein, that detects early
lesions of the cervix. It is
expressed by cells within the lesion but not the normal cervix. We now wish to determine if it will aid
in the diagnosis of cervical lesions of those women who repeatedly receive a Pap
smear diagnosis of ASCUS.
We have also tested the
ASCUS-diagnosed Pap smears for the presence or absence of high risk human papillomavirus (HPV) types.
In our analysis we have
screened both conventional Pap smears and a relatively new procedure of
preparation, termed Thin Prep Pap smears.
In the conventional Pap smears, we observed that in those smears with a
corresponding high grade lesion (CINII/III) in the tissue biopsy of the cervix
we detected MN/CAIX- expressing atypical and normal cells in 100% of cases. We also detected MN/CAIX expression of
normal cells only in 50% of smears with a tissue biopsy that was diagnosed as
benign, atypia or low grade lesion (CINI). Thus, in conventional Pap smears we were
able to detect all high grade lesions.
However, there is a high rate of false positives (approximately
50%). Despite this, we conclude
that MN/CAIX negative ASCUS-diagnosed conventional Pap smears indicate that the
patient does not harbor a significant lesion. This represents approximately 50% of all
ASCUS-diagnosed women in this study.
Unfortunately, we encountered
false negatives in the Thin Prep Pap smear study. Our initial data suggest two reasons for
this: the destruction of the MN/CAIX atigen with the
fixation procedure used; and the relatively small number of cells, including
atypical cells, in the Thin Prep smear.
Our screening for high risk HPV
types also indicated false negatives in those smears from patients harboring a
significant lesion.
Most recently, we have begun
testing a new biomarker, p16, that looks promising but too few cases have been
examined.
In conclusion, we believe it is likely that multiple biomarkers will be needed to adequately identify those ASCUS cases that harbor a significant lesion, with acceptable limits of sensitivity and specificity.
1.
Cheng Y, Chakrabarti R, Garcia-Barcelo M, Ha TJ, Srivatsan ES, Stanbridge EJ, Lung
ML. Mapping
of nasopharyngeal carcinoma tumor-suppressive
activity to a 1.8-megabase region of chromosome band 11q13. Genes Chromosomes Cancer. 2002 May;34(1):97-103.
2.
Srivatsan
ES, Chakrabarti R, Zainabadi
K, Pack SD, Benyamini P, Mendonca MS, Yang PK, Kang K, Motamedi D, Sawicki MP, Zhuang Z, Jesudasan RA, Bengtsson U, Sun C, Roe BA, Stanbridge EJ, Wilczynski SP,
Redpath JL.
Localization of deletion to a 300 Kb interval
of chromosome 11q13 in cervical cancer. Oncogene.
2002 Aug 15;21(36):5631-42.
3.
Kaluz S,
Kaluzova M, Stanbridge EJ.
Ezpression of
the hypoxia marker carbonic anhydrase IX is critically
dependent on SP1 activity. Identification of a novel type of hypoxia-responsive
enhancer. Cancer Res. 2003 Mar 1;63(5):917-22.
4.
Kaluzova M,
Kaluz S, Lerman MI, Stanbridge EJ. DNA damage is a prerequisite for p53-mediated
proteasomal degradation of HIF-1alpha in hypoxic cells
and downregulation of the hypoxia marker carbonic
anhydrase IX. Mol
Cell Biol. 2004 Jul;24(13):5757-66.
5.
Mendonca
MS, Farrington DL, Mayhugh BM, Qin Y, Temples T, Comerford K,
Chakrabarti R, Zainabadi K,
Redpath JL, Stanbridge EJ,
Srivatsan ES.
Homozygous deletions within the 11q13
cervical cancer tumor-suppressor locus in radiation-induced, neoplastically transformed human hybrid cells. Genes Chromosomes Cancer. 2004 Apr;39(4):277-87.