Annual Meeting Proceedings Part 1 - American Society of Clinical ...

190s Developmental Therapeutics—Experimental Therapeutics
3068 General Poster Session (Board #16B), Mon, 8:00 AM-12:00 PM
Integrated next-generation sequencing and patient-derived xenografts to
personalized cancer treatment. Presenting Author: Elena Garralda, Clinical
Research Programme. Spanish National Cancer Research Center (CNIO),
Madrid, Spain
Background: The knowledge of actionable somatic genomic alterations
present in each tumor is making possible the era of personalized cancer
treatment. Methods: Using massively parallel sequencing we performed
whole exome sequencing analysis of tumor and matched normal blood
samples of 8 patients (2 pancreatic adenocarcinoma, 1 neuroendocrine
tumor, 1 glioblastoma, 1 uveal melanoma, 1 colon cancer) to identify
putatively actionable tumor specific genomic alterations. We used 2 in
silico methods (Polyphen and SIFT) to estimate the functional significance
of a given confirmed mutation. Primary xenografts (PDX), generated by
direct engraftment of tumor samples from the patients into immunocompromised
mice, were used as an in vivo platform that provided the opportunity
to test proposed personalized medicine strategies. Results: At this time
exome sequencing analyses have been performed for 5 patients (1 patient
died prematurely, 1 tumor sample was insufficient, 1 result is pending).
More than 30 million bases of target DNA were analyzed in the tumor and
normal samples in every case, with at least 70 distinct reads at each base.
Tumor specific mutations (Muts) and copy number variations (CNVs) were
identified: 5 Muts in the neuroendocrine tumor; 62Muts/6CNVs and
38Muts/10CNVs in the pancreatic tumors; 63Muts/23CNVs in the glioblastoma;
5 Muts in the melanoma. All samples profiled contained actionable
alterations with the most relevant mutations affecting NF1, PTPN11,
EPHA3, CDKN2A, FAS (glioblastoma); PI3KCA, ARID1A, ARID1B, DDR2,
SMAD4, TP53, KRAS, PTCHD3 (pancreatic); CREB3L3, ITPR2 (neuroendocrine);
GNA11, TAOK3 (melanoma). PDX from the pancreatic cancer
patient was treated with a PI3K inhibitor and dasatinib, reported to be
effective in discodin domain receptor 2 (DDR2) mutant cancer with no
effect. Accordingly treatment of that patient with dasatinib was not
effective and the level of this mutation in the tumor was observed to be low.
Conclusions: Detection of actionable tumor-specific genomic alterations in
the clinical setting is feasible. In silico methods and primary xenografts can
help in the challenge of linking confirmed mutations to protein function
and ultimately to clinical utility.
3070 General Poster Session (Board #16D), Mon, 8:00 AM-12:00 PM
OM-RCA-01, an FGFR1 specific humanized antibody for the treatment of
renal cell carcinoma (RCC). Presenting Author: Ilya Tsimafeyeu, Kidney
Cancer Research Bureau, Moscow, Russia
Background: Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a
potential therapeutic target for the treatment of metastatic RCC. We
investigated the preclinical activity of OM-RCA-01, a novel therapeutic
humanized anti-FGFR1 antibody with high affinity (Kd of 1.59 nM), in
RCC. Methods: To assess the effect of anti-FGFR1 antibody on FGFmediated
signaling, the human renal carcinoma Caki-1 FGFR1-expressing
cells were dosed with OM-RCA-01 at 100, 10, and 1 mcg/ml. Control wells
were left untreated. Three hours after dosing, bFGF was added at a
concentration of 50 ng/ml. Additional control wells were treated with
OM-RCA-01 without FGF-stimulation. Cell growth inhibition was determined
using Promega’s Cell Titer-Glo assay. CR female NCr nu/nu mice
were set up with 1 mm3 Caki-1 tumor fragments sc in flank. Tumor sizes
were measured in a blind fashion twice a week with a vernier caliper. Mice
with established tumors were randomly divided into vehicle, non-specific
IgG or OM-RCA-01 groups per 10 animals in group. Endpoint was
significant differences in tumor growth delay. Results: In vitro study showed
that bFGF increased proliferation of the human FGFR1-expressing renal
carcinoma cells (p�0.011). OM-RCA-01 antibody significantly inhibits
FGF-triggered cell proliferation in comparison with control. In vivo, the
tumors in untreated mice or mice treated with non-specific IgG continued
their aggressive growth to reach the size of 2000 cm3, at which point the
mice were killed. In contrast, treatment with OM-RCA-01 not only significant
arrested further growth of the tumors (p�0.006) but also demonstrated
differences in tumor volume compared with vehicle already on Day
13. A similar anti-tumor activity of OM-RCA-01 was observed when the
antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (p�0.917).
Administration of 10 mg/kg antibody for up to 35 days resulted in minimal
body weight loss and no observations of gross toxicity were made.
Conclusions: Targeting FGFR1 blocks FGF/FGFR1 pathway in RCC. Monoclonal
antibody OM-RCA-01 has significant early anti-tumor efficacy in
Caki-1 xenograft model. Isolated blocking of FGFR1 by low-dose antibody
could be safe and effective.
3069 General Poster Session (Board #16C), Mon, 8:00 AM-12:00 PM
CD30 expression in nonlymphomatous malignancies. Presenting Author:
Jeff Porter Sharman, Willamette Valley Cancer Institute and Research
Center, Eugene, OR
Background: CD30 is commonly expressed in Hodgkin lymphoma (HL),
anaplastic large cell lymphoma (ALCL), and testicular embryonal carcinoma.
Expression of CD30 in other solid tumors and non-lymphomatous
malignancies has been reported but not investigated systematically. CD30
is the target of brentuximab vedotin (Adcetris), an antibody drug conjugate
(ADC) that is approved for the treatment of patients with relapsed HL and
systemic ALCL after failure of other therapies. A study was initiated to
determine the incidence of CD30 expression in non-lymphomatous malignancies
and to identify patients who may be candidates for treatment with
brentuximab vedotin. Methods: Patients with non-lymphomatous malignancies
were eligible for screening if they were relapsed or refractory to
previous therapy or had no effective treatment options available. Archived
tissue from solid tumors was tested for CD30 expression by immunohistochemistry
(IHC); fresh bone marrow or blood samples from multiple
myeloma or leukemia patients were tested by flow cytometry. Patients were
considered CD30 positive and eligible for a companion treatment protocol
with brentuximab vedotin if �10% of malignant cells stained positive by
IHC or �20% by flow cytometry. Results: At this interim analysis, a total of
875 patients have been tested for CD30 expression: 95% had solid tumors,
3% had leukemia, and 2% had multiple myeloma. Twenty-two patients
(2.5%) were CD30 positive, including 7 of 94 patients with ovarian cancer
(7%), 5 of 20 with melanoma (25%), 2 of 5 with mesothelioma (40%), 1 of
4 with skin squamous cell carcinoma (25%), 2 of 41 with triple negative
breast cancer (5%), 1 of 37 with pancreatic cancer (3%), 1 of 26 with
small cell lung cancer (4%), and 1 of 3 with anal cancer (33%), and thyroid
carcinoma (33%). One patient was identified with CD30-positive mast cell
leukemia. In positive patients, the percent of CD30-positive malignant
cells varied between 10 and 80%. Conclusions: CD30 expression was
observed in multiple types of non-lymphomatous malignancies, thereby
identifying additional populations who may be candidates for treatment
with a CD30-targeted ADC, such as brentuximab vedotin. A companion
clinical trial with brentuximab vedotin is currently ongoing.
3071 General Poster Session (Board #16E), Mon, 8:00 AM-12:00 PM
Clinical significance of PRL-3 genomic amplification/expression profiles
and preclinical study of PRL-3 inhibitor in human gastrointestinal cancers.
Presenting Author: Keishi Yamashita, Kitasato University School of Medicine,
Sagamihara, Japan
Background: PRL (phosphatase of regenerating liver) is a tyrosine phosphatase
that dephosphorylates molecules involved in cancer invasion and
metastasis and subsequently activates either PI3 kinase or Src pathway.
PRL-3 was initially identified as a gene that is amplified in metastasis of
colorectal cancer. We are thinking much of clinical potential of PRL-3
inhibitor as a molecular targeted therapy in GI cancer. Methods: Immunohistochemistry
and genomic status were assessed for PRL-3 in esophageal
squamous cell carcinoma (ESCC)(n�88), gastric adenocarcinoma (n�173),
and colorectal adenocarcinoma (n�107).RNA interference was used to
determine its specific functional roles in GI cancers. Preclinical study using
PRL-3 inhibitors (1-4-bromo-2-benzylidene rhodanine) was performed in 4
ESCC and 4 gastric cancer cell lines that were intensely expressed for
PRL-3, or TE5 which showed basal level expression. Results: (1) PRL-3
expression is associated with lymph node metastasis in primary ESCC
(p�0.0012), gastric adenocarcinoma (p�0.0001), and colorectal carcinoma
(p�0.0001). In the primary tumors with lymph node metastasis, its
expression was recognized in 96, 80, 86%, respectively. (2) If restricted to
patients with PRL-3 expression, genomic amplification was found exclusively
in stage IV ESCC (30%), and stage III/IV gastric cancer (40%). In
colorectal cancer, PRL-3 genomic amplification is found in 35% of stage
III/IV, but only in 10% of stage II (p�0.002). (3) PRL-3 RNA interference
robustly suppressed metastatic cancer phenotypes. (4) PRL-3 inhibitor
suppressed phenotypes as well in a dose dependent manner (0, 1, 10, and
50 mM). Interestingly, 10 mM of the inhibitor could not suppress muscle
cell (C2C12) that endogenously express PRL-3, but 50 mM suppressed it.
Conclusions: PRL-3 inhibitor has a great clinical potential to suppress
tumors with metastatic ability, that was represented by lymph node
metastasis or recurrent disease of GI cancers.
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