Presented by Georgios Karagkounis, MD at the SS05: Colorectal 1 session during the SAGES 2017 Annual Meeting. March 22, 2017
Good afternoon we have nothing to disclose our group has previously reported that the pathologic response to nirav and chemo radiation is quantified by the ajcc scoring system predict survival in rectal cancer as you can see here patients with a score of zero which indicates a complete response have the best long-term outcomes while those with scores one through
Three do worse we have also shown that statin therapy during near adjuvant chemo radiation was associated with improved response a significantly greater percentage of patients on statin therapy that shipped complete or near complete response here you can see that 65% of patients had scores 0 to 1 as opposed to less than 50% of patients who were not on statin therapy
A popular current approach to cancer biology involves the cancer initiating cell model where tumor initiation and maintenance are driven by an epigenetically distinct subpopulation of tumor cells with the ability to proliferate extensively self renew and generate new tumors these cells have been termed cancer initiating cells from here on in this presentation cics
Or cancerous stem cells and they have been involved in modern approaches to colorectal cancer biology cics can be isolated from fresh patient humors after associating the tumor into single cells and sorting four cells with a surface marker cd44 which has been linked to cic properties interestingly we found that in our pretreatment rectal cancer samples increased
Expression of the cd44 gene was associated with increased resistance to radiation as you can see in this graph suggesting a role for cics in radiation sensitivity before making too large a leap into clinical translation we wanted to take our bedside observations back to the bench to sort out this phenomenon we hypothesized that cics mediated rectal cancer resistance
To radiation and also that statin therapy targets cics and combined with radiation results in greater cic inhibition in order to test our hypothesis we use patient derived tumor cells both cics and differentiated non cics in each case the interventions included a control condition simvastatin alone radiation alone and a combination of simvastatin and radiation
And our endpoints were cell viability and sphere formation which is a hallmark characteristic of in-vitro cic function we started by assessing the effects of radiation alone on the viability of cics and differentiated cells from the same patient here you can see the results in samples from two patients where cells were allowed to grow for five days after treatment
The graph depicts the relative fall change and viability in each condition relative to control at each time point on the top of its graph the black line depicts the cic population from its sample which only suffers a limited decrease in viability despite the high radiation dose of sixth grade on the contrary the red line depicts the differentiated cells which are
Essentially obliterated five days after irradiation these findings are in accordance with the modern theory that relatively radio resistant subpopulations of tumor cells those cics may be responsible for human regrowth after therapy we then evaluated the effects of simvastatin on each cell population again in samples from two different patients differentiated
Cells depicted with a black line on the top of the graph showed no inhibition essentially from one micromolar of simvastatin which is a relatively low concentration on the other hand cics are significantly inhibited by simvastatin based on these findings we evaluated whether the addition of similar stat into radiation could lead to increased ciency inhibition
In this next figure cics from two patients were treated with irradiation either alone or with two different those concentrations of simba statin and the viability of the cultured cells was measured relative to daily zero through ten days as you can see radiation alone on top with a black line resulted in an almost on him unhindered increase in viability for the
Duration of the experiment while the combination treatment was significantly more effective in inhibiting cic viability and these effects increase with higher simvastatin doses to demonstrate that the effects of silver studying are not limited to cell viability but also included cic function we measured the sphere forming ability of cics from two patients the
Defining characteristic of in vitro cic function here again the control condition which is depicted by the blue bars on the left of the graph of each graph and then as you can see irradiation alone which is the first red bar only modestly decreased the percentage of cics that were able to form spheres however the addition of simvastatin resulted in a dose-dependent
Significantly enhanced inhibition of the sphere forming capacity of cics indicating that there cic phenotype was compromised by our therapy in summary we showed that cics are more resistant to radiation than non cics from the same tumor however the inverse is true for simvastatin cics exhibits simvastatin sensitivity even at relatively low doses whereas known cics
Do not silver statin therapy therefore allows targeting the radio resistant cic cell population to increase the efficacy of radiation on colorado cancer cells in vitro in conclusion the information presented here supports the use of the cic model in rectal cancer and combined with her previous clinical observation is a source of excitement as we plan for the use
Of statins in both rectal cancer animal models and more importantly clinical trials i would like to thank my mentor dr. the lady for offering me the opportunity to work on this project and the fellow members of the lab for their assistance and of course this research would not be possible without the generous support of our society stages that along with phase ers
Funded project thank you request can you remind me what the mechanism is that simba statin affects the cics so so this is actually an important question that we’re trying to address the theory is that even those things i said and all statins are administered in clinical practice to lower cholesterol levels what we have measured is that the effect that they have the
Entire neoplastic effect that they have both in colorectal cancer and other tumors are actually not because of the diminishing number concentrations of cholesterol that they cause but rather other intermediaries that are crucial cofactors in signaling cascade within the cells so we know for instance that the rafts honka protein which we know in colorectal cancer in
The form of k wrasse needs one of those intermediaries as a necessary cofactor to function therefore once blocking that pathway k res doesn’t function as well and cells that are reliant on this do not are inhibited thank you very much for your excellent paper but and in the majority of surgical groups we’re trying to reduce the number of patient ingredient rather
In protocol so rather barbeque mo therapy aromatherapy and now i use suggestion you know try to come back to the past using this drug you know to try to reduce but to try to increase the pathological complete response for example in patient we there with the t3 b or maybe hi rectum you know you are suggesting again is to use this drug with rather therapies right
Not to operate those patients or to operate so so this this would be obviously that the ultimate long-term goal would be to find a preoperative neoadjuvant therapy model that essentially reduces the need or even remove the need from surgery and we can move to a point where people we can spare patients are protected from the protecta me and all the morbidity that
That entails but based on the data that we have so far we were not any position near to be able to recommend this for clinical practice but rather to start working on clinical trials that may show improved response and if that is true hopefully extend the parameters of patients that actually receive it thank you okay
Transcribed from video
Simvastatin Enhances Radiation Sensitivity of Colorectal Cancer by Targeting Colorectal Cancer Initi By Society of American Gastrointestinal and Endoscopic Surgeons (SAGES)
