Proffered Papers Sessions
`
`9
`
`nucleotide exchange. Further mechanistic studies revealed that through
`steric hindrance the compounds block the formation of
`the Ras-SOS
`complex, a key intermediate of the exchange reaction. At the cellular level,
`our compounds inhibit the formation of active RasGTP and prevent Ras
`signaling to downstream effectors. To define the potential clinic utility of
`these compounds, we performed biological characterization of Ras-driven
`tumors and identified a subset of Ras mutant tumors that depend on
`nucleotide exchange factors for the activation of Ras, suggesting a specific
`profile for the use of exchange inhibitors.
`Conclusions: We conclude that
`the compounds act as competitive
`inhibitors of nucleotide exchange to prevent the activation of Ras. The
`discovery of a binding pocket on Ras with functional significance represents
`a breakthrough finding that will offer a new direction for therapeutic
`intervention of the Ras oncoprotein. Our findings provide new opportunities
`to target the “undruggable” Ras oncoprotein.
`
`Breast Cancer − Advanced Disease
`Sunday 25 September 2011, 09:00−11:35
`16LBA
`LATE BREAKING ABSTRACT
`Reversal of Tamoxifen Resistance (Hormone Resistance) by Addition
`of Sirolimus (mTOR Inhibitor) in Metastatic Breast Cancer
`
`G.S. Bhattacharyya1, J. Biswas2, J.K. Singh3, M. Singh4, K. Govindbabu5,
`A.A. Ranade6, H. Malhotra7, P.M. Parikh8, T. Shahid9, S. Basu9.
`1Orchid Nursing Home/AMRI, Medical Oncology & Clinical Hematology,
`Kolkata, India; 2CNCI, Director, Kolkata, India; 3Mahavir Cancer
`Sansthan, Director, Patna, India; 4Mahavir Cancer Sansthan, Medical
`Oncology, Patna, India; 5ICON-ARO, Medical Oncology, Bangalore,
`India; 6ICON-ARO, Medical Oncology, Pune, India; 7 ICON-ARO, Medical
`Oncology, Jaipur, India; 8ICON-ARO, Medical Oncology, Mumbai, India;
`9AMRI, Radiation Oncology, Kolkata, India
`
`Introduction: The estrogen receptor was first proven therapeutic target
`identified in breast cancer cells.
`Because it is present in 50−75% of breast cancer and has direct correlation
`with cancer phenotype ER modulation has been in main stay of treating
`this disease in this phenotype in last 40 years. A key protein in the
`pathway tumorogenesis is AKT kinase which antagonises the hormone
`therapy like Tamoxifen because of cross-tak. In fact Tamoxifen resistance
`are associated with high levels of activity of AKT.
`mTOR (mammalian Target Of Rapamycin) inhibitors block the downstream
`pathway of AKT and addition of this to Tamoxifen may overcome resistance
`to Tamoxifen.
`Materials and methods: The study was done in two phases
`a. In metastatic breast cancer patients who were ER/PgR positive and
`HER-2 negative and could not afford AI inhibitors were randomised
`to Tamoxifen (20 mg once a day) or Tamoxifen with Sirolimus (2 mg
`per day).
`b. In patients who had failed AI and/or Tamoxifen were randomised to the
`above combination also.
`Each phase had 200 patients that is total 400 patients.
`All patients had ER/PgR, HER-2/neu, KI-67 done.
`The primary end point was Response Rate and Time to Progression.
`Secondary end points were Safety, Toxicity and Preliminary Pharmacoeco-
`nomic Analysis.
`Results: The results of
`the phase I study showed response rate of
`36% vs 68% (average ER status 4 to 8, median = 6) and time to
`progression − 9 months vs 16 months.
`The phase II study showed response rates of 4% vs 40% and time to
`progression − 3 months vs 11 months.
`The study was done for the period 2004–2010, single center with 3 referral
`centers. The combination was effective and safe.
`The Sirolimus used was of certified and generic version. Tamoxifen was of
`certified and generic version.
`Conclusion: Pharmacoeconomic analysis shows it to be cost effective
`combination with a good toxicity profile.
`
`Conclusions: BIBF 1120 in combination with mFOLFOX6, for first-line
`mCRC has a similar magnitude of efficacy and safety/tolerability profile
`but lower incidence of SAE in comparison to BEV. Detailed analysis of
`SAEs is ongoing.
`Funded by Boehringer Ingelheim; ClinicalTrials.gov NCT00904839.
`
`BIBF 1120 arm
`(n = 85)
`
`BEV arm
`(n = 41)
`
`Pts with AE Grade (cid:2)3 by MedDRA preferred
`terms (cid:2)5%, %
`Neutropenia
`Diarrhoea
`Neurotoxicity
`Paraesthesia
`Asthenia
`Decreased appetite
`Thrombocytopenia
`Peripheral neuropathy
`Abdominal pain
`Polyneuropathy
`Serious AEs (SAE), %
`AEs leading to discontinuation of, %
`BIBF 1120 or BEV
`FOLFOX
`Pts receiving all planned mFOLFOX6 cycles in
`first 6 months, %
`5-FU
`Oxaliplatin
`Total mFOLFOX6 cycles, median
`5-FU
`Oxaliplatin
`Median treatment exposure, days
`5-FU
`Oxaliplatin
`
`88
`
`32
`15
`14
`13
`11
`8
`6
`5
`4
`2
`34
`
`25
`34
`
`66
`32
`
`14
`10
`
`212
`158
`
`95
`
`24
`12
`10
`12
`10
`2
`2
`7
`5
`5
`54
`
`32
`29
`
`63
`17
`
`13
`9
`
`219
`160
`
`Proffered Papers Sessions
`
`Basic Science/Translational Research
`Monday 26 September 2011, 14:45−17:10
`15LBA
`LATE BREAKING ABSTRACT
`Drugging the Undruggable: Small-molecule Inhibition of Ras
`Oncoprotein
`
`G. Fang1, T. Maurer2, L. Garrenton1, N. Skelton3, B. Fauber3, S. Malek4,
`A. Giannetti4, P. Jackson1, J. Rudolph3, W. Wang2. 1Genentech Inc.,
`Cell Regulation/Oncology, South San Francisco CA, USA; 2Genentech
`Inc., Structural Biology, South San Francisco CA, USA; 3Genentech
`Inc., Discovery Chemistry, South San Francisco CA, USA; 4Genentech
`Inc., Biochemical Pharmacology, South San Francisco CA, USA
`
`Background: Ras is a nucleotide-dependent switch that converts from an
`inactive GDP-bound state to an active GTP-bound state when activated by
`guanine nucleotide exchange factors, such as SOS. Active RasGTP then
`binds to and activates downstream signaling effectors. Ras is the most
`frequently mutated oncogene and hyperactive mutant Ras constitutively
`signals to effectors to promote cell survival, proliferation and metastasis.
`Thus, Ras oncoprotein has been considered by the cancer community to
`be one of the most important oncology drug targets. Despite the enormous
`interest and extensive exploratory efforts in industry and academia, small
`molecules that bind to Ras in a well-defined manner and exert inhibitory
`effects have not been uncovered to date. We describe in this abstract the
`identification and characterization of small-molecule inhibitors of the Ras
`oncoprotein.
`Materials and Methods: To explore a new means of directly targeting
`Ras, we used a fragment-based lead discovery approach via an NMR-
`based screen. Hits from the fragment screen were characterized for their
`interactions with Ras by NMR and X-ray crystallography and for their effects
`on Ras activation and signaling in reconstituted biochemical assays in vitro
`and in cellular assays in vivo.
`Results: From the fragment-based screen, we identified a group of
`small molecules that each bind to a common site adjacent to the switch
`I/II regions in the Ras protein. X-ray crystallography studies of
`three
`compound-Ras complexes indicate that the binding site can be expanded
`upon ligand binding. Nucleotide exchange factors, notably SOS, are
`required to convert inactive RasGDP to active RasGTP. We determined that
`the compound-binding site is located at the interface of Ras and SOS.
`A subset of our Ras-binding molecules indeed inhibited SOS-mediated
`
`PAR-ZORT-000806
`
`NOVARTIS EXHIBIT 2178
`Par v Novartis, IPR 2016-00084
`Page 1 of 1