The American Association for Cancer Research (AACR) holds its annual meeting this coming Saturday, March 31 through Wednesday, April 4, 2012. This meeting is the "lead-in" to oncology's largest annual meeting - ASCO, in June. The AACR Annual Meeting highlights the best and latest findings in all major areas of cancer research. Investigators in a variety of disciplines will attend and benefit from hearing about these advances and networking with their colleagues. While most of the meeting focuses on pre-clinical activity and pre-clinical studies, some of the meeting will have early to late-state human studies available for presentation. Many of the abstracts and discussions at AACR have direct implications on future trial-design, and rationale for further exploration of a particular molecule/drug compound in a particular oncology indication. In this paper, we are going to focus on certain areas of scientific development that we think have broader implications in human studies currently underway, and could possibly be an insight into positive or negative outcomes within these human studies.
We feel these abstracts provide the rationale for the upside surprises in companies mentioned over the near and longer term.
Threshold Pharmaceuticals (THLD)
Monday, April 2, 2012 (10:30 am)
Randomized phase II study of the efficacy and safety of gemcitabine + TH-302 (G+T) vs gemcitabine (G) alone in previously untreated patients with advanced pancreatic cancer
M. J. Borad, Mayo Clinic Cancer Center - Arizona, Scottsdale, AZ
Discussant: Malcolm J. Moore, University of Toronto University Health Network, Toronto, Canada
**The presentation will report the detailed results from the randomized Phase 2b trial of the efficacy and safety of gemcitabine plus TH-302 versus gemcitabine alone in previously untreated patients with advanced pancreatic cancer.
Ariad Pharmaceuticals (ARIA) and Merck (MRK)
Monday, April 2, 2012 (1:00 pm)
Vorinostat abrogates ridaforolimus-induced activation of Akt in synovial sarcoma cells: A possible rationale for their synergism
Background: Curative treatments for patients with metastatic synovial sarcoma (SS) do not exist and such patients have a poor prognosis. Previously, we demonstrated that the combination of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat exhibited synergism in a variety of cell lines. Here, we explore whether the Akt pathway is potentially involved in mediating the synergistic effects of ridaforolimus and vorinostat.
Conclusions: The combination of ridaforolimus and vorinostat demonstrates in vitro synergism in SS as well as in a variety of other tumor types. The addition of vorinostat prevented ridaforolimus-induced Akt activation, a possible mechanism of resistance to mTOR inhibition. Adding HDAC inhibition to mTOR inhibitors may be a route to circumvent Akt-mediated resistance to mTOR inhibitors. Our results also indicate that this combination may demonstrate broad anti-neoplastic activity.
**(Our opinion) These pre-clinical findings could provide the thesis for a potential positive outcome in the current Phase 1 study "A Phase I Study of Ridaforolimus and Vorinostat in Patients With Advanced Renal Cell Carcinoma (RCC)"
Monday, April 2, 2012 (8:00 am)
Response biomarkers to IGF1R and mTOR inhibitor combination therapy in ovarian carcinoma
Ovarian cancer, the sixth most frequent cause of cancer death among women in the developed world, is a heterogeneous disease characterized by a diverse set of genetic alterations. These factors underscore the need for more effective treatment options accompanied by biomarker strategies to identify patients who will have a greater likelihood to respond to novel therapy. A combination strategy to target the PI3K pathway with the mTOR inhibitor ridaforolimus and anti-IGF1R antibody dalotuzumab is currently undergoing clinical development. Previous translational work has suggested that low RAS activity, as determined by a RAS gene expression signature score, and high levels of IGF1R pathway activation may enrich for response to this combination therapy. Ranking of tumors in the Moffitt tumor database with a low RAS and high IGF profile suggested that ER+ breast and ovarian cancers are enriched for these putative response biomarkers. Consistent with these observations, clinical responses were noted for several ER+ breast or ovarian cancer patients in a Phase I trial for ridaforolimus and dalotuzumab combination therapy. To provide further support for low RAS and high IGF as response biomarkers, the anti-tumor activity of ridaforolimus and dalotuzumab was assessed in 12 patient derived primary ovarian cancer xenograft models developed at START. These models have been extensively characterized by the South Texas Accelerated Research and Therapeutics (START) group for response to standard of care drugs, and the status of many commonly mutated genes in ovarian cancer. Molecular analyses of these tumors suggest that they represent a diverse cross section of ovarian cancer. Similarly, responses to ridaforolimus and dalotuzumab combination therapy ranged from minimal to significant regression. Importantly, the responsive tumor models were associated with a low RAS gene signature and a moderate to high IGF expression level. Tumors with KRAS mutations or a high RAS gene score were generally resistant to therapy. These results support the further development of low RAS and high IGF as enrichment biomarkers for ridaforolimus and dalotuzumab combination therapy in ovarian carcinoma.
**(Our opinion) These pre-clinical findings could provide the thesis for a potential positive outcome in two current human studies: Phase II "A Study of Ridaforolimus (MK-8669) in Combination With Dalotuzumab (MK-0646) Compared to Standard of Care Treatment in Estrogen Receptor Positive Breast Cancer Patients" and Phase 1 "A Study of Dalotuzumab + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + MK-8669 Combination Therapies in Participants With Advanced Cancer"
As previously discussed the Hedgehog signaling pathway, when activated, appears to be a crucial regulator of angiogenesis and metastasis. Mutations in the hedgehog pathway genes are prevalently the cause of basal-cell carcinoma (BCC), as well as a subset of medulloblastoma patients. Curis and Roche's Erivedge (GDC-0449/vismodegib) was recently approved for treatment of advanced BCC patients with possible label-expansion use in patients with basal-cell nevus syndrome and operable BCC. Curis and Roche estimate this is a >$1 billion/year drug in this one small indication, of which Curis is entitled to royalties. (see slide 13 for Erivedge results).
The hedgehog signaling pathway is also thought to regulate production of tumor growth via a "ligand mechanism" (this is entirely different from the "mutation" mechanism which directly causes the tumor growth). Therefore, the "ligand mechanism" does not play a direct role in tumor growth, but may serve as a regulator or "assistant" in tumor growth. Cancer indications such as pancreatic, small-cell lung cancer, stomach, gastroesophageal junction and certain breast cancers are thought to have hedgehog "ligand" involvement.
In our previous article, we discussed Curis and Roche's possible blockbuster with vismodegib if their multiple human studies show efficacy in pancreatic cancer. There are currently six (6) ongoing early to mid-stage trials with vismodegib in the pancreatic indication. Vismodegib is also being tested in combination with other drugs in small-cell lung cancer, breast, prostate, sarcoma, multiple myeloma as well as gastroesophageal cancer.
We would like to highlight a few pre-clinical abstracts which provide the rationale for success in SCLC, gastroesophageal indications, and pancreatic (there are actually 65 sessions related to hedgehog at AACR):
Sunday, April 1, 2012 (4:50 pm)
The crosstalk of mTOR/S6K1 and Hedgehog pathways
Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States, and TNFα/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation of Gli1, downstream effector of hedgehog pathway, has been observed in EAC. In this study, we found that activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by mTOR pathway inhibitor enhances the killing effects of the hedgehog pathway inhibitor. Together, our results established a crosstalk between mTOR/S6K1 and the hedgehog pathways, which provides not only a new mechanism for non-canonical hedgehog pathway but also a rationale for combination therapy for EAC.
Article: Scientists link 2 cancer-promoting pathways in esophageal cancer
**mTOR and hedgehog provides the rationale for a recent study combining an mTOR-agent (sirolimus) and vismodegib entitled "Sirolimus and Vismodegib in Treating Patients With Solid Tumors or Pancreatic Cancer That is Metastatic or Cannot Be Removed By Surgery"
Tuesday, April 3, 2012 (8:00 am)
The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+-homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells
Cisplatin-resistance is an important issue in lung cancer. The hedgehog signaling pathway (HH) has been shown to be activated in cancer. GDC-0449 is a low-molecular Hh pathway inhibitor that binds to and inhibits Hh pathway receptor SMO. It is the first systemic SMO-inhibitor that has entered clinical trials. Recently, we could show that GDC-0449 is effective in lung cancer cell lines and that combination with cisplatin gives an additional effect. However, no data on the effect of GDC-0449 on cisplatin-resistant lung cancer cells are available.
We aimed at investigating if the hedgehog pathway inhibitor GDC-0449 is effective in cisplatin-resistant cells and if it alters the intracellular Ca2+-homeostasis. The cytoplasmatic ([Ca2+]cyto) and endoplasmatic ([Ca2+]ER) Ca2+-concentration of HCC (adeno carcinoma of the lung) and H1339 (small cell lung carcinoma) cells was measured with the calcium indicator dye Fura-2 AM. The expression of the inositol-1,4,5-trisphosphate receptor (IP3R) and Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) were analyzed using Western Blot analysis.
GDC-0449 inhibited cell growth in cisplatin-naïve and -resistant cells. In both cell types, GDC-0449 increased [Ca2+]cyto and reduced endoplasmatic [Ca2+]ER. Cisplatin failed to considerably alter the Ca2+-homeostasis in resistant cells. The effects of GDC-0449 on the intracellular Ca2+-homeostasis were not mediated by an altered expression of IP3R or SERCA. We demonstrate that GDC-0449 alters the intracellular Ca2+-homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells.
**(Our opinion) These pre-clinical findings could provide the thesis for a positive outcome in the current Phase 2 study (which is due for readout later this year) entitled: "Cisplatin and Etoposide Phosphate With or Without GDC-0449 or Cixutumumab in Treating Patients With Extensive-Stage Small Cell Lung Cancer"
Monday, April 2, 2012
Sonic hedgehog signaling and Androgens are linked in tumor-stromal interaction through Epithelial-Mesenchymal transition (EMT) in prostate cancer progression
Backgrounds: Sonic hedgehog (Shh) signaling is known to relate to cancer progression but the detail about how to correlate and link with another signaling is debating. The purpose of this study is to investigate the link between Shh signaling, androgens and epithelial-mesenchymal transition (EMT) in prostate tumor-stroma interaction during prostate cancer ((PCa)) progression.
Conclusions: Shh signaling is involved in tumor-stromal interaction through a link with Androgens and EMT, and thus plays a pivotal role in PCa progression. Cyclopamine may therefore be a possible therapeutic agent for blocking PCa progression.
**(Our opinion) This pre-clinical work could provide a thesis for a positive outcome in the following Phase 1-2 study entitled "Leuprolide Acetate or Goserelin With or Without GDC-0449 Followed by Surgery in Treating Patients With Locally Advanced Prostate Cancer"
Wednesday, April 4, 2012
Hedgehog pathway is a novel therapeutic target in tamoxifen resistant breast cancer that protects from autophagic cell death and is aberrantly activated by PI3K/AKT signaling
Aims: Approximately 30-40% of patients with estrogen receptor positive (ER+) invasive breast cancer relapse despite targeted endocrine therapy with tamoxifen (TAM). Alternative cell survival mechanisms aberrantly activated over time supports tumor growth, upon blockade of estrogen dependent pathways by TAM. We have earlier identified Hedgehog (Hhg) signaling pathway as an alternative survival pathway activated in TAM resistant ER+ tumors (SABC Abst# 851859, 2011; S-9, 2010). We sought to determine if activation of Hhg pathway is critical for survival of the resistant cells, the mechanism underlying activation of this pathway, and determine if targeting such tumors with Hhg inhibitor would improve outcomes.
Conclusions: Our work has demonstrated for the first time that activated Hhg signaling is an alternate survival mechanism for TAM resistant breast cancer. A cross talk between Hhg pathway, MYC and p53 protects TAM-resistant cells from autophagy related cell death. PI3K/AKT signaling pathway plays a key role in activating this pathway in TAM-resistant cells. Furthermore, targeting these tumors with anti-Hhg therapy inhibited tumor growth and could be combined with PI3K inhibitor for additional benefit. Clinical trials using this combination in patients with advanced ER+ breast cancer are warranted and are under development
Wednesday, April 4, 2012
Eliminating pancreatic cancer metastases through inhibition of hedgehog and RAS signaling
Pancreatic cancer is arguably one of the most challenging human malignancies, with the five year survival rate below 5%. Pancreatic cancer is often found in advanced stages, and is unresponsive to conventional cancer therapy. Thus, the need to develop novel treatment strategies targeting metastasis of pancreatic cancer has never been greater. The molecular hallmark of pancreatic cancer is an activating mutation in the small GTPase KRAS. Unfortunately, efforts to target RAS signaling are not very successful for pancreatic cancer treatment. Recently, inhibition of hedgehog signaling emerges as a new cancer therapeutic option, but the available data from several current clinical trials in pancreatic cancer show only modest activity. At present, gemcitabine is the standard chemotherapy for metastatic pancreatic cancer but the response rate is less than 10%, with the median survival of only 6-7 months. A new chemotherapy combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) was recently studied in Europe with a response rate of 30% and median survival of 11 months, but at a cost of significant toxicity.
In order to design treatment strategies based on the molecular changes critical for cancer metastasis, we took the advantage of the knowledge recently generated in our laboratory and the newly developed molecularly targeted drugs currently in clinical trials. We compared primary pancreatic tumors with metastatic liver tumors for molecular alterations in an orthotopic mouse model, and discovered elevated expression of Indian hedgehog (Ihh) and ERK1/2 phosphorylation in liver metastases. Inhibition of Hh signaling or MEK activity alone reduced primary tumor size but did not significantly affect distal tumor metastases. In contrast, targeting Hh signaling and MEK activity in the orthotopic mouse model dramatically decreased the primary tumor size and nearly eliminated lung and liver metastases. Mice treated with two inhibitors lived two weeks longer than those in other groups. While MEK inhibition mainly interefered with cell proliferation, suppression of ligand-dependent Hh signaling affected the tumor microenvironment. These data indicate that simultaneous suppression of RAS and Hh signaling will be more effective in future pancreatic cancer treatment.
Sunday, April 3, 2012
The predictive value of a 5-gene signature as a patient pre-selection tool in medulloblastoma for Hedgehog pathway inhibitor therapy
Medulloblastoma (MB), an invasive primitive neuroectodermal tumor of the posterior fossa, is the most common brain tumor in children, comprising ~20% of childhood and <2% of adult brain tumors. Current standard of care treatment, surgery followed by craniospinal radiation and chemotherapy, can lead to significant long term toxicities, especially in very young patients. At the time of relapse, no standard salvage therapy exists. Therefore, targeted therapies are needed. Several studies have used gene expression profiling to identify distinct molecular subgroups of MB, including one characterized by activated Hedgehog signaling. Using available gene expression data, a 5-gene Hh signature that can be assayed in formalin-fixed paraffin-embedded (FFPE) samples by standard RT-PCR was identified.
Sunday, April 1, 2012
Gas1 and Kif27 genes are strongly up-regulated biomarkers of Hedgehog inhibition (PF-04449913) on leukemia stem cells in Phase I Acute Myeloid Leukemia and Chronic Myeloid Leukemia treated patients
Hedgehog pathway activation contributes to leukemia development and growth, and that targeted pathway inhibition is likely to offer an efficient therapeutic opportunity. PF-04449913, a Hh pathway inhibitor, is a new selective and potent inhibitor of leukemia self-renewal and is currently being evaluated in phase I clinical trials.
Conclusions: This data demonstrates that PF-04449913 specifically targets the Hh Pathway in CD34+ cells, suggesting that Hh inhibition may impair leukemia stem cell maintenance. In addition, we identify several new potential biomarkers (e.g. Gas1 and KIF27). Taken together, these data may be useful for pts selection strategies and subsequent eradication of the LSC
Infinity Pharmaceuticals (INFI)
Tuesday, April 3, 2012
Hedgehog pathway inhibition delays regrowth of ovarian cancer following paclitaxel and carboplatinum only if initiated immediately after completion of chemotherapy
Malignant activation of the Hh pathway through the signaling protein Smoothened (Smo) occurs in a broad range of cancers, including ovarian. IPI-926 is a potent orally delivered small molecule that targets the Hh pathway by inhibiting Smo. Recent studies from our laboratory provide evidence that IPI-926 slows serous ovarian cancer growth in a primary human tumor xenograft model. More importantly, IPI-926 delays the resurgence of tumor growth typically observed after cytoreduction with paclitaxel and carboplatinum (T/C) treatment.
Our data suggest that blocking Hh pathway activity immediately following chemotherapy maintains and prolongs the inhibitory effect of chemotherapy on ovarian tumor growth. The absence of an IPI-926-mediated inhibition of tumor resurgence following a 14-day delay in treatment supports the concept that there is a critical period for tumor re-establishment. Our data, along with those of others, suggest that the early stages of ovarian tumor re-growth may be dependent on Hh pathway signaling.
We believe the pre-clinical work being discussed at AACR's annual meeting will have direct impact on current and future trial designs and drug combination rationale.
We remain long CRIS and believe shares are not being appropriately valued at its current market-cap valuation of ~$350 million. We expect readout on Phase 2 combination studies in gastroesophageal and small-cell lung cancer studies later this year, as well as at least one pancreatic study at ASCO in June, 2012. Again, we think there is potential 150-200% possible upside with a positive reading in any one of their upcoming trials in indications other than BCC.
While we have no positions in ARIA, THLD, PFE, NVS, INFI, MRK or RHHBY, we believe these abstracts could provide upside to their pipelines over the coming quarters and years.
With the pre-clinical work we have highlighted in this writing, we believe there is a reasonable chance we will see positive outcomes in these aforementioned studies. However, this is only our thesis. Drug development is difficult, and many times, pre-clinical xenograft and mouse-model work does not equate to success in humans. We believe going forward, however, highly targeted molecules and intelligent drug design will enable greater success from pre-clinical to human studies.
Please due your own due diligence and provide your own rationale to potential outcomes.