DAY 1 SUMMARY OF KEY EDUCATIONAL SESSIONS
The Current Progress of Several c-Met Inhibitor Programs
On the first day at the AACR conference, we attended an educational session that reviewed the important roles of c-Met,
the different strategies used to inhibit c-Met, as well as the clinical data of several c-Met inhibitors currently under
development.
The c-Met associated signaling pathway plays an important role in several essential biologic events including mitogenesis
and morphogenesis. Constitutive activation of c-Met signaling leads to endothelial cell proliferation, angiogenesis, and
tumor metastasis. Evidence has been increasing which supports the association between c-Met signaling and many
different types of tumors. Due to the essential role of c-Met signaling and its association with cancer, this field is very
active with many participants developing inhibitors targeting the c-Met signaling pathway. There are three major
strategies to develop drugs that inhibit the c-Met pathway:
• Developing antagonists that inhibit ligand-receptor interactions;
• Developing inhibitors that directly inhibit c-Met activity; and
• Developing inhibitors that block the interaction between intracellular receptors and effectors.
Dr. Patricia M. LoRusso from Karmanos Cancer Institute, Wayne State University, reviewed the clinical data from several
of the c-Met inhibitors:
ARQ-197 (ARQL, Market Outperform) has demonstrated promising antitumor activity in a Phase 1 trial with 3
partial responses (PRs) observed in 35 evaluable patients treated with a intermittent dosing of ARQ-197 (13 out
of 35 patients had either PR or SD longer than 6 months and 17 out of 35 patients had PR or SD longer than 4
months). In addition, 7 patients had SDs among 10 patients receiving a continuous dosing of the drug. Of
importance, ARQ-197 has also demonstrated a very mild toxicity profile with no dose limiting toxicity (DLT)
observed in the Phase 1 trial. The maximum tolerated dose (MTD) of ARQ-197 (120 mg bid) was actually
determined by pharmacokinetic data. There were also no drug related grade 3 or 4 adverse events and the most
common side effects were the typical non-specific events such as fatigue and anemia. ARQ-197 is currently in a
broad Phase 2 program targeting multiple cancer indications, with the potential to report data from 2H08 and
beyond.
XL-880 is an agent targeting both c-Met and VEGFR2. In a Phase 1 trial, out of 52 evaluable patients XL-880
induced 5 PRs, 9 MRs (minor responses) and 11 stable diseases (>3months) including renal cell carcinoma
(RCC), melanoma, ovarian cancer, etc. The drug is also well tolerated with no grade 4 adverse events. Currently
XL-880 is under development in a Phase 2 trial for the treatment of papillary renal carcinoma. Out of 19
evaluable patients, 15 patients had tumor shrinkage as the best response and 12 out of 16 patients had stable
disease longer than six months. GlaxoSmithKline (GSK, Not Rated) has assumed the development of XL-880.
The data from the Phase 2 programs will be updated at the 2008 American Society of Cancer Oncology (ASCO)
annual conference later this year.
XL-184 is another small molecule inhibitor targeting both c-Met and VGEFR2. In a Phase 1 trials with 44 patients,
2 patients had confirmed PRs, 2 had unconfirmed PR and 14 had SDs (range between 3 to 20 months).
Lastly, AMG-102 is a fully human monoclonal antibody which targets SF-HGF, thereby inhibiting the binding of
SF-HGF to the c-Met receptor and preventing the activation of the c-Met signaling pathway. While AMG-102
shown potential single agent activity in both in vivo and in vitro models, the drug did not induce an objective
clinical response in a Phase 1 trial of 31 patients (13 patients or 42% had SDs).
Based on the current available data, Dr. LoRusso found these c-Met inhibitors programs appear to be “promising”, but
“not exciting”. Going forward, she believes that combination therapy may be a better approach than targeting c-Met
signaling alone unless compelling single agent activity is observed. In fact, in a poster to be presented later in the
conference at this year’s AACR meeting (abstract #1336), the simultaneous inhibition of both c-met and EGFR is shown
to generate synergistic antitumor effects in preclinical models.
Cancer Stem Cells: A Not so Novel Idea Continues to Gain Momentum
At the first day’s proceedings we attended an educational session entitled “The Cancer Stem Cell Hypothesis: Biological
and Clinical Implications”. The room, which was overflowing with spectators, came to learn about new evidence
implicating a subcomponent of cancer cells that drive tumorgenesis and possess the unique properties of self-renewal

and differentiation. Max S. Wicha, from the University of Michigan Comprehensive Cancer Center provided the
background for the “cancer stem cell hypothesis” as well as the rationale for why this hypothesis represents a paradigm
shift in our understanding of how cancer arises. He was followed by Dr. William H. Matsui from Johns Hopkins University
School of Medicine, who spent time highlighting the preclinical results as well as some preliminary clinical data
surrounding several compounds in the clinic that may target the cancer stem cell niche.
Dr. Wicha began his talk by listing the pathways integral to stem cells. These include: 1) Hedgehog (HH); 2) Notch (N); 3)
BMI-1; 4) Wnt; and 5) PTEN. While HH and N are both key players involved in cell fate decisions, both pathways
intersect and affect BMI-1, a key regulator of self-renewal. Interestingly, according to the presenter, the same pathways
known to be regulated in normal stem cells, is de-regulated in the case of tumorgenesis. In fact, molecular profiling can
detect sub-populations of cells that express the downstream targets of HH, N, and Wnt signaling including CD44 (target of
Wnt signaling), CD24 (negative regulator of CXCR4), and aldh1 (intracellular detoxification enzyme). Of note, Dr. Wicha
stressed that cancer cell populations expressing aldh1 were typically higher grade tumors, had higher proliferative rates,
and were more proficient in invading the surrounding tissue (metastasis). Finally, the presenter concluded with an
astonishing explanation of the cancer stem cell hypothesis: cancer stem cells do not come from tissue specific normal
stem cells. In other words, a cancer stem cell does not come to life, because an endogenous stem cell somehow loses
the ability to self regulate. Rather, the cancer stem cell arises from a sub-population of regular cancer cells that have
acquired the ability to self renew and differentiate.
Dr. Matsui initially presented the notion that distinct tumor cell populations exist in multiple myeloma. In fact, the focus of
his work is to identify markers which allow for the separation of these distinct cell populations. His group has identified
CD138 negative cells as a population of cells that can re-instigate cancer, whereas CD138 positive cells, while still
cancerous, cannot. Interestingly, these cells are very resistant to chemotherapy and radiation. Factors that could be
driving this resistance include: active efflux of cytotoxic agents utilizing the ABC transporter; intracellular detoxification
enzymes (aldh1); and the fact that these cells are naturally quiescent and have low expression of target proteins. Another
marker/target on the stem cell is telomerase. Telomerase is highly active in stem and progenitor cells and is a common
feature in many types of cancers. Dr. Matsui highlighted his work with Geron’s (GERN, Market Perform) telomerase
inhibitor, GRN163L, and that in his experiments, approximately 70-90% inhibition of CD138 negative cells was seen. In
animal models, the relative clonegenic frequency came close to zero when mice were exposed to GRN163L.
Interestingly, this compound affects both compartments of cells, including the CD138 negative cells (presumably the
cancer stem cell) and CD138 positive cells (cancer cells). Dr. Matsui concluded his talk by highlighting the challenges of
developing a cancer stem cell therapeutic in the clinic including:
1) standard response criteria will not accurately assess the efficacy of the drug the responses are likely to be
delayed;
2) conversely, one can assume that if the cancer stem cell is successfully targeted, whatever responses are seen
should be durable; and
3) combination therapy beginning with the initiation of chemotherapy to target a large population of cancer cells,
followed by a stem cell specific therapeutic to kill off the remaining cancer stem cells will most likely be the way
such therapeutics are evaluated in the clinic.
What is the take home point for investors? Watch this cancer stem cell space closely – it has the potential to radically
change the way we view and treat cancers going forward.
Hedgehog signaling pathway gets more visibility on AACR’s first day.
In a well attended Educational Session, Genentech’s (DNA, Market Outperform) Frederic J. de Sauvage updated the
scientific community about Hedgehog (HH) signaling and laid the ground work for upcoming data presentations on
Sunday and Monday. HH is an extracellular protein that binds to a receptor called Patched (PTCH) on the cell membrane.
Activated Patched releases its negative control over an adjoining receptor called Smoothened (SMTH), consequently
triggering a cascade of intracellular signaling events leading to cell proliferation. HH signaling is fundamentally promoted
by SMTH, which is under a constant state of inhibition by the PTCH receptor. SMTH is being seen by drug companies as
the key druggable target in the HH signaling pathway. HH signaling has been implicated in multiple malignant solid tumors
including pancreatic, prostate, small cell lung, hepatocellular and breast cancers. To date, the HH pathway is best
characterized in the pathogenesis of two types of tumors: basal cell carcinoma (a type of skin cancer) and
medulloblastoma (a type of brain tumor). In medulloblastoma mutations are commonly seen in the PTCH receptor
resulting in a lack of regulation of SMTH receptor consequently causing uncontrolled HH signaling resulting in tumor
formation. We point out that Infinity’s (INFI, Market Perform) IPI-926 targets the SMTH receptor. As well, Genentech has
in-licensed a small molecule HH antagonist from Curis (CRIS, Not Rated). A word of caution was offered to the scientific
community that there are unanswered questions regarding the off target effects of HH antagonists.