A Phase 2 Evaluation of Irofulven as Second-line Treatment of Recurrent or Persistent Intermediately Platinum-Sensitive Ovarian or Primary Peritoneal Cancer A Gynecologic Oncology Group Trial

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Abstract
This multicenter phase 2 trial was conducted by the Gynecologic Oncology Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial ovarian cancer. Eligible patients had documented recurrent ovarian cancer 6 to 12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0 to 2, and adequate bone marrow, hepatic, and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in Solid Tumors. Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7 partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 months (1.3-37.5 months) and 22.1 months or more (2.8-57.8+ months), respectively. Patients received a median of 3 cycles (range, 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia. Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.

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A Phase 2 Evaluation of Irofulven as Second-line
Treatment of Recurrent or Persistent Intermediately
Platinum-Sensitive Ovarian or Primary Peritoneal Cancer
A Gynecologic Oncology Group Trial
Russell J. Schilder, MD,* John A. Blessing, PhD,Þ Mark S. Shahin, MD, þ David S. Miller, MD
Krishnansu Sujata Tewari, MD,|| Carolyn Y. Muller, MD, David P. Warshal, MD,**
Scott McMeekin, MD,ÞÞ and Jacob Rotmensch, MDþþ
Abstract: This multicenter phase 2 trial was conducted by the Gynecologic Oncology
Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial
ovarian cancer.
Eligible patients had documented recurrent ovarian cancer 6 to 12 months after receiving a
front-line platinum-based regimen and no other chemotherapy. Patients were required to
have measurable disease, performance status of 0 to 2, and adequat e bone marrow, hepatic,
and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously
on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in
Solid Tumors.
Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7
partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-
free and overall sur vival were 6.4 months (1.3Y37.5 months) and 22.1 months or more
(2.8Y57.8+ months), respectively. Patients received a median of 3 cycles (range, 1Y21) of
protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and
thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with an-
orexia and another with hypomagnesemia.
Irofulven administered at this dose and schedule was well tolerated but had modest activity
as a single agent.
ORIGINAL ARTICLE
International Journal of Gynecological Cancer
&
Volume 20, Number 7, October 2010 1137
*Department of Medical Oncology, Fox Chase Cancer Center,
Philadelphia, PA; Gynecolo gic Oncology Group Statistical and Data
Center , Roswell Park Cancer Institute, Buf falo, NY; Abington Me-
morial Hospital, Abington, PA; §University of Texas Southw estern
Medical Center at Dallas, Dallas, TX; ||University of California Medi-
cal Center , Irvine, CA; Univ ersity of New Mexico Cancer CenterV
South, Albuquerque, NM; **Cooper Hospital/Univ ersity Medical
Center, Camden, NJ; ††Univ ersity of Oklahoma, Oklahoma City, OK;
and ‡‡Rush Presbyterian St Luke’s Medical Center, Chicago, IL.
Address correspondence and reprint requests to Russell J.
Schilder, MD, Department of Medical Oncology, Fox Chase
Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111.
E-mail: russell.schilder@fccc.edu.
This study was supported by National Cancer Institute grants
CA 27469 (Gynecologic Oncology Group) and CA
37517 (Gynecologic Oncology Group Statistical and Data
Center). This study was also supported in part by grants P50
CA083638 (Seiden, PI) and CA006927 (S eiden, PI) from
the National Cancer I nstitute.
The following Gynecologic Oncology Group member institutions
participated in this study: Abington Memorial Hospital, Walter Reed
Army Medical Center, Northweste rn University/Feinber g School of
Medicine, University of Mississippi, Colorado Gynecologic
Oncology Group, University of P ennsy lv ania Cancer Center ,
Univ ersity of Texas Southw e stern Medical Center at Dallas,
University of California Medical Center at Irvine, Rush Presbyterian
St Luke’s Medical Center, State Uni ver sity of New York Do wnsta te
Medical Center, Uni versity of New Mexico Health Sciences
Center , Cooper Hospital/Uni v ersi ty Medical Center , Columbus
Cancer Council/Ohio State, Uni versity of Massachusetts Memorial
Health Care, Univers ity of Oklahoma, Univ ers ity of Vir gin ia Health
Sciences Center , Uni ver sity of Chicago, Case Western Reserve
University, Tampa Bay Cancer Consortium, Gynecologic
Oncology Network/Brody School of Medicine, University of
TexasV Galveston, and Community Clinical Oncology Program.
Copyright * 2010 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1111/IGC.0b013e3181e8df36
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
Key Words: Irofulven, Platinum-sensitive ovarian cancer, Primary peritoneal cancer, GOG
Received March 19, 2010, and in revised for m May 6, 2010.
Accepted for publication May 20, 2010.
(Int J Gynecol Cancer 2010;20: 1137Y1141)
E
pithelial ovarian cancer remains the leading cause of gy-
necologic cancer death among American women. Ap-
proximately 21,550 women were diagnosed in 2009 and an
estimated 14,600 died of this disease.
1
More than 70% of
the patients have a diagnosis of advanced-stage disease.
2
Initial management includes cytoreductive surgery followed
by platinum/taxane-based chemotherapy. Although approxi-
mately 80% of women will have no detectable disease at
the end of front-line treatment, most of them will recur and
require further therapy.
3
The clinical effica cy of retreatment
with platinum-based chemotherapy is limited by the devel-
opment of drug resistance. Therefore, new chemotherapeutic
agents with novel mechanisms of action are needed in the
treatment of this disease.
Irofulven (MGI-114, 6-hydroxymethylacylfulvene) is a
unique cytotoxic agent that is related to the jack-o’-lantern
(Omphalotus illudens) mushroom-derived illudin toxins. It
is a semisynthetic derivative of the sesquiterpene, illudin S,
which binds to DNA and produces DNA single-strand breaks
leading to cell cycle arrest in S phase and cell death through
caspase-mediated apoptosis.
4
Irofulven has a more favorable
therapeutic index than its parent illudin S. Resultant apo-
ptosis is independent of p53 status, multidrug resistance, bcl-
2 expression, and mis match repair enzymes.
5
It also binds to
RNA and proteins. Radiolabeled irofulven localizes primar-
ily in the nuclear compartment followed by the cytosolic and
membranous compartments.
6
In vitro, irofulven was active
against numerous cell lines known to be resistant to alkylat-
ing agents, cisplatin, doxorubicin, topoisomerase inhibition,
and taxanes.
7Y9
In preclinical models, the drug works syn-
ergistically with topotecan, platinum compounds, taxanes,
and radiotherapy.
Early clinical trials with irofulven revealed that the
agent has significant toxicity on certain schedules. The con-
secutive daily schedule for 5 days demonstrated antitumor ac-
tivity in a number of tumors including ovarian and endometrial
cancers but was associated with severe gastrointestinal (GI),
renal, metabolic, hematologic, and ocular toxicities.
10Y12
Ex-
ploration of alternative doses and schedules demonstrated im-
proved tolerability while maintaining the antitumor activity of
the study drug. In a phase 1 trial exploring weekly and biweekly
schedules of administration of irofulven, a patient with heavily
pretreated recurrent ovarian cancer who received irofulven on
days 1 and 8 schedule every 21 days had a complete response
that lasted 11 months.
13
The maximum tolerated dose was
determined to be 18 mg/m
2
for a dosing schedule of days 1 and
8 every 21 days not to exceed 0.55 mg/kg per infusion and
50 mg total dose per infusion. Based on these data, the dose of
0.45 mg/kg per infusion was chosen for further evaluation in
this phase 2 trial.
METHODS
Patient Selection
Patients with persistent or recurrent platinum-sensitive
epithelial ovarian or primary peritoneal carcinoma were eli-
gible for this trial. Patients must have received a platinum/
taxane-based chemotherapeutic regimen for the management
of primary disease, which may have included consolation or
extended therapy after surgical or nonsurgical assessment.
Patients may not have received chemotherapy for recurrent
disease. Patients were considered platinum sensitive and el-
igible if they had progressed between 6 and 12 months of
their last platinum dose. Patients who progressed more than
12 months from their last platinum dose were not eligible, as
retreatment with platinum-based therapy is routinely used in
this setting. Measurable disease defined by Response Eval-
uation Criteria in Solid Tumors was required.
14
Other eligi-
bility criteria included (1) Gynecologic Oncology Group
(GOG) performance status of 0 to 2; (2) adequate bone
marrow (absolute neutrophil count Q 1500/KL and platelet
count 9 100,000/KL), hepatic (transaminase and alkylating
phosphatase levels e 2.5 the upper limit of institutional
normal [ULIN] tota l bilirubin level e 1.5 ULIN) and renal
functions (serum creatinine level e ULIN); (3) no grade 2 or
higher peripheral neuropathy; (4) no radiation to more than
25% of marrow-bearing areas; (5) no myocardial infarction,
cerebrovascular events, transient ischemic attacks, or con-
gestive heart failure in the past 6 months before enrolling on
the trial; (6) no electrocardiogram evidence of acute ischemia
or significant conduction abnormality (bifascicular block,
defined as left anterior hemiblock in the presence of right
bundle branch block; second or third degree atrioventricular
blocks); (7) no other invasive malignanc ies with the excep-
tion of nonmelanomatous skin cancer in the past 5 years; (8)
negative serum pregnancy test result if still of childbearing
potential; (9) no histor y of retinopathy and/or macular de-
generation; and (10) no prior therapy with irofulven. All
women provided written informed consent, and participating
institutions obtained annual institutional review board ap-
proval in accordance with federal, state, and local institutional
requirements and guidelines.
Drug Administration
Patients received irofulven at a dose of 0.45 mg/kg in-
travenously for 30 minutes on days 1 and 8 every 21 days.
Doses were not to exceed 50 mg for each infusion. Cycles were
administered every 21 days until disease progression or unac-
ceptable toxicity. Progression was determined radiologically.
Toxicities were graded according to the National Cancer In-
stitute Common Toxicity Criteria (CTC) version 2.0.
Schilder et al International Journal of Gynecological Cancer
&
Volume 20, Number 7, October 2010
1138 * 2010 IGCS and ESGO
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
Pretreatment and Follow-up Studies
Pretreatment evaluation consisted of history and phy-
sical examination, assessment of GOG performance sta-
tus, chest radiograph, electrocardiogram, complete blood cell
count, serum chemistries (lactate dehydrogenase, blood urea
nitrogen, creatinine, magnesium, calcium phosphate, trans-
aminase, alkaline phosphatase, and total bilirubin levels),
urinalysis, cancer antigen 125 test, and documentation of
measurable disea se by computed tomography. During the
study, interval history, physical examination, toxicity assess-
ment, complete blood cell count, serum chemistries, and
cancer antigen 125 test were obtained at the start of each
cycle. Computed tomography to evaluate response was per-
formed every 2 cycles. Evaluation of response was by Re-
sponse Evaluation Criteria in Solid Tumors.
14
Subsequent
cycles were not administered until the absolute neutrophil
count was 1500/KL or more, and the platelet count was
100,000/KL or more. Therapy was allowed to be delayed up to
a maximum of 2 weeks. Patients who did not recover blood
counts to the aforementioned parameters or did not recover
nonhematologic toxicity to a grade lower than 1 by the end of
this 2 week period would be removed from study. Doses would
be reduced to 0.35 mg/kg (first level reduction) or 0.25 mg/kg
(second dose-level reduction) for febrile neutropenia, grade
4 neutropenia lasting more than 7 days, grade 4 thrombocy-
topenia, grade 2 or higher renal toxicity, grade 3 or higher
hepatic toxicity, grade 3 or higher GI toxicity unresponsive to
medical treatment, or grade 2 or higher nonhematologic tox-
icity with an impact on vital organ function. Patients who
experienced any degree of decrease in vision would have
irofulven dosing discontinued until the condition had fully
reversed. If treatment was restarted, the dose of irofulven was
reduced by 25%. Continuation of therapy after experiencing
visual symptoms, grade 1 or 2, without decrease in vision, was
left up to the patient and treating investigator; a dose decrease
of 25% was permitted. There were no dose re-escalations on
this trial.
Statistical Design and Methods
A GOG phase 2 trial of cisplatin in this disease yielded
a response rate of 24%. As a result, this agent has been used
extensively in combination chemotherapy. A more recent
study of taxol demonstrated a response rate of approximately
36%. In effect, these are the standards against which other
phase 2 trials must be measured. Twenty-two additional
agents have been examined in this setting. Response rates
ranged from 0% to 18% with only 6 agents having a response
rate in excess of 10%. Consequently, if a new agent has a
response rate of 15% or less, it will be of no clinical signif-
icance. Conversely, if the true response rate is at least 30%,
further study is clearly indicated.
15,16
The study used a 2-stage accrual design
17
with an early
stopping rule in the event that treatment demonstrated in-
sufficient activity. During the first stage of accrual, 22 to
29 patients would be entered and evaluated. If at least 4
responses were observed among the first 22 to 24 patients, or
at least 5 responses of 25 to 29 patients, a second phase of
accrual was to be initiated that would increase accrual to 53 to
60 patients. The regimen would be considered active if at
least 11 responses were observed among 53 patients, at least
12 responses were observed among 54 to 57 patients, or at
least 13 responses among 58 to 60 patients. If the true re-
sponse rate is 1 5%, the mean probability of designating the
treatment as active is limited to 10%. Conversely, if the true
response rate was 30%, then the probability of correctly
classifying the treatment as active was 90%.
RESULTS
Sixty-one women were enrolled onto the trial. Two
patients were ineligible owing to incorrect cell type (1) and a
platinum-sensitive interval of more than 12 months (1). Four
patients were inevaluable, as they never were treated, leaving
55 evaluable patients. Patient characteristics are provided in
Table 1. Al l patients had prior platinum-based chemotherapy,
and 1 patient had prior radiotherapy (to liver).
Adverse Events
Patients received a median of 3 cycles (1Y21) of pro-
tocol therapy. There were no treatment-related deaths. Grade
4 hematologic toxicity was limited to reversible neutropenia
and thrombocytopenia. One GI (anorexia) and one metabolic
(hypomagnesemia) grade 4 toxicities were observed (Table 2).
Other significant (grade 3) nonhematologic toxicities included
metabolic and neurological adverse effects. There were 5
grade 3 ocular toxicities. Two patients had photophobia, 1 had
flashing lights and floaters, and the last 2 patients had blurred
vision.
Efficacy
The overall response rate was 12.7% (7/55). There were
no complete respon ses. Thirty patients had a best response of
stable disease (54.6%) with a median duration of 8.2 months
(2.6Y37.5 months; Table 3). The median progression-free
survival is 6.4 months (1.3Y37.5 months) with a median
TABLE 1. Patient demographics (n = 55)
Age, median (range), yr 58 (35Y80)
Performance status
040
113
22
Histological diagnosis
Serous 47
Endometrioid 2
Mixed 3
Undifferentiated 3
Prior treatment
Prior chemotherapy 54
Prior chemo/radiation 1
International Journal of Gynecological Cancer
&
Volume 20, Number 7, October 2010 Irofulven as Treatment of Ovarian Cancer
* 2010 IGCS and ESGO
1139
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
overall survival of 22.1 months or more (2.8Y57.8 months;
Fig. 1). The response rate was 16.7% (4/24) in the first stage
of accrual.
DISCUSSION
Initial phase 2 trials of irofulven in patients with re-
current gynecologic malignancies were based on consecutive
daily schedules for 4 or 5 days repeated every 28 days.
10,11
Although the drug was shown to have activity, these trials
were fraugh t with major toxic effects. These included sig-
nificant neutropenia , thrombocytopenia, nausea with eme-
sis, and severe electrolyte abnormalities with renal tubular
acidosis that occasionally culminated in treatment-related
deaths.
Subsequently, more intermittent dosing schedules were
explored that demonstrated more favorable toxicity pro-
files.
13
Two dosing schedules were recommended for further
phase 2 testing: days 1 and 8 every 21 days at 18 mg/ m
2
per
infusion or days 1 and 15 every 28 days at 24 mg/m
2
per
infusion. There were n o treatment-related deaths with either
of these regimens. Significant GI toxicity was rare with the
schedule of days 1 and 8 every 21 days. Hematologic toxicity
was slightly more pronounced with this schedule compared
with the schedule of days 1 and 15 every 28 days. The in-
cidence of a visual toxic effect did not seem to depend
on duration of infusion. There was an association between
dose per infusion and occurrence of a visual toxic effect.
The mean (SD) dose per infusion in patients with a vi-
sual toxic reaction was 23.6 (3.9) mg/m
2
compared with
20.2 (4.1) mg/m
2
in patients without a visua l toxic reaction.
The risk of visual toxic effects seemed to be even more ac-
curately predicted by dosing based on body weight than body
surface area. Patients with visual toxic reactions received
a mean (SD) dose of 0.65 (0.09) mg/kg compared with
0.53 (0.12) mg/kg in patients without visual toxic reactions.
Sophisticated ophthalmologic examination and pathologic
evaluations demonstrated that a visual toxic effect is based on
selective cone loss in the retina.
18,19
The incidence of a visual
toxic effect was much lower in patients who received less than
0.55 mg/kg and a total maximum dose of 50 mg per infusion,
hence, the basis for dosing at 0.45 mg/kg for this trial with a
limit of 50 mg per infusion.
The response rate on this intermittent dosing schedule
is 12.7%. This rate of response was in patients who were
platinum sensitive by the definition of recurrence within 6 to
12 months of their last platinum dose. The response rate was
even lower in a similar study conducted by Seiden et al
12
in
which patients had platinum-sensitive or resistant disease.
The response rate was slightly higher (22%) in the study by
Sarosy et al
11
who evaluated the daily dosing schedule of
5 days every 28 days but with greater toxicity. The higher
response rate in the latter trial, of course, may not be a
function of schedule but an artifact of comparing trials with a
small number of patients with varying eligibility criteria.
Although irofulven clearly induces some tumor shrink-
age, its antitumor activity may ultimately be limited by the
inability to increase the dose given its toxicities. As a DNA-
damaging agent, irofulven may combine well with other drugs
FIGURE 1. Kaplan-Meier plots of progression-free and
overall survival.
TABLE 2. Toxicities (grade 3/4; n = 55)
Grade 3 Grade 4
Leukopenia 11 0
Thrombocytopenia 11 2
Neutropenia 16 6
Other heme 6 V
Constitutional 4 V
GI 8 1
Infection 4 V
Musculoskeletal 2 V
Metabolic 2 1
Neuropathy (sensory) 1 V
Other neurologic 2 V
Ocular 4 V
Pain 1 V
TABLE 3. Best responses (n = 55)
n%
Partial 7 (12.7)
Stable disease 30 (54.6)
Progressive disease 12 (21.8)
Inevaluable 6 (10.9)
Response duration, mo 8.2 (2.6Y37.5)
Progression-free survival, mo
Median (range) 6.4 (1.3Y37.5)
Overall survival, mo
Median (range) 22.1+ (2.8Y57.8)
Schilder et al International Journal of Gynecological Cancer
&
Volume 20, Number 7, October 2010
1140 * 2010 IGCS and ESGO
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
with complementary mechanisms of action and toxicity pro-
files that will allow for reduction in dose and therefore toxi-
cities. The combination of irofulven and irinotecan was found
to be feasible in a phase 1 trial, although there were few
responses.
20
Irofulven produces DNA damage largely ignored
by the nucleotide excision repair system. The single-strand
DNA breaks induced by irofulven suggest that the drug
maybe highly active in BRCA-deficient tumor cells analogous
to poly(ADP-ribose) polymerase inhibitors. This synergistic
mechanism of action of DNA damage between irofulven and
other DNA-damaging agents may stem from the nucleotide
excision repair system being overwhelmed at 2 distinct points
in the pathway, leading to the prolonged presence of stalled
polymerases eventually triggering apoptosis as a consequence
of collisions with the replication fork resulting in additional
lethal secondary DNA damage. DNA damage induced by
irofulven is enhanced when combined with platinum or alky-
lating agents in preclinical models.
8,9
Irofulven at low nontoxic
doses in combination with either of the angiogenesis inhibitors,
anginex and topomimetic 0118, was more effective at inhibit-
ing tumor growth in mice bearing human xenografts than full
doses of irofulven.
21
Anginex is a 33mer designer peptide that
targets galectin-1, which is unregulated in tumor-activated
endothelial cells. Galectin-1 is necessary for tumor cells to
adhere to and migrate on the extracellular matrix. Topomimetic
0118 is a calyx[4] arene-scaffold surface topomimetic that
embodies the molecular dimensions, surface topology, and
chemical composition of anginex but has greater biological
activity.
Based on all of the data, including our results presented
here, irofulven will not have a role in the treatment of ovarian
cancer as a single agent. Its future may lie in combinations
with newer agents such as angiogenesis antagonists or inhi-
bitors of DNA repair, such as poly(ADP-ribose) polymerase
inhibitors, smac mimetics, or bcl-2 antagonists (such as BH3
mimetics).
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International Journal of Gynecological Cancer
&
Volume 20, Number 7, October 2010 Irofulven as Treatment of Ovarian Cancer
* 2010 IGCS and ESGO
1141
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    • "However, an enhanced anti-tumor activity of irofulven was observed in combination with other anticancer agents (Poindessous et al. 2003; Serova et al. 2006; Kelner et al. 2008), other anti-angiogenic or chemotherapeutic drugs (Alexandre et al. 2004; Woo et al. 2005; Hilgers et al. 2006; Dings et al. 2008). Irofulven produced different results in phase I and II trials of human cancer cell lines, including advanced melanoma (Pierson et al. 2002), advanced renal cell carcinoma (Alexandre et al. 2007) and pretreated ovarian carcinoma6 Chemical structures of cordycepin (36), and cytotoxic terpenoids (37–44) from Flammulina velutipes Fungal Diversity (2013) 62:1–40(Seiden et al. 2006; Schilder et al. 2010). In addition to these investigations, another class of semisynthetic analogs of the natural product illudin S, acylfulvenes (AFs) serve as a useful tool for evaluating protein and nucleic interactions, and considerable cytotoxic activities (Pietsch et al. 2011). "
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  • [Show abstract] [Hide abstract] ABSTRACT: Most oncology compounds entering clinical development have passed stringent preclinical pharmacology evaluation criteria. However, only a small fraction of experimental agents induce meaningful antitumor activities in the clinic. Low predictability of conventional preclinical pharmacology models is frequently cited as a main reason for the unusually high clinical attrition rates of therapeutic compounds in oncology. Therefore, improvement in the predictive values of preclinical efficacy models for clinical outcome holds great promise to reduce the clinical attrition rates of experimental compounds. Recent reports suggest that pharmacology studies conducted with patient derived xenograft (PDX) tumors are more predictive for clinical outcome compared to conventional, cell line derived xenograft (CDX) models, in particular when therapeutic compounds were tested at clinically relevant doses (CRDs). Moreover, the study of the most malignant cell types within tumors, the tumor initiating cells (TICs), relies on the availability of preclinical models that mimic the lineage hierarchy of cells within tumors. PDX models were shown to more closely recapitulate the heterogeneity of patient tumors and maintain the molecular, genetic, and histological complexity of human tumors during early stages of sequential passaging in mice, rendering them ideal tools to study the responses of TICs, tumor- and stromal cells to therapeutic intervention. In this commentary, we review the progress made in the development of PDX models in key areas of oncology research, including target identification and validation, tumor indication search and the development of a biomarker hypothesis that can be tested in the clinic to identify patients that will benefit most from therapeutic intervention.
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