Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§

Signup to see this grant's details

Preclinical Investigation Toward a Clinical Trial of Combination, Multimodality Treatment for DIPG
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

DIPG is an aggressive childhood brain tumor that is nearly always fatal. Although most past patients have died of the tumor pushing on the brainstem’s pons area, DIPG spreads to other parts of the brain and spinal cord, known as the central nervous system (CNS). To cure DIPG, we will need to combine treatment to the main tumor in the pons and the widespread tumor too. We know that radiation treatment to the pons helps temporarily in DIPG but is not enough. We have shown that radiation to the rest of the CNS limits tumor spread, but even this isn’t enough. Chemotherapy has not been effective in the past, but new techniques like injecting medicine directly into the tumor, and new drugs that attack DIPG’s weaknesses, are starting to work. None of these will be enough individually, though. In this project, we will study combinations of radiation and chemotherapy, delivered both to the main tumor and the entire CNS, to find an approach that is most effective against DIPG in mouse models. We will also be developing this combination in parallel as a clinical trial that we believe will mark the beginning of true hope and better survival for patients.

 

Our past work on a project funded by The Cure Starts Now demonstrated key findings very important to this new project. We showed that even though oral or IV chemotherapy has not worked against DIPG in clinical trials, it can reach the tumor tissue enough to have a potential effect. We also built models in the lab of radiation to the entire CNS and to the pons alone in mice growing human DIPG in the pons. With this model, we showed that radiation to the entire CNS can limit spread of the tumor. Finally, we also built a model of chemotherapy injected directly into the pons and showed that we could get much higher levels of chemotherapy into the tumor than by giving it by IV.

 

We will now build on this work by studying how we can combine all these treatments together to control both local and widespread DIPG. We have chosen to study medicines that have already shown signs of working in DIPG and are in clinical trials, so that it will be very practical to develop a new combination trial. These medicines are called ONC201, panobinostat, ribociclib, selinexor, and carboplatin. We will use our models of human DIPG growing in a dish, and in the pons of mice, to test lots of combinations of medicines and radiation delivered directly to the tumor and to the whole CNS. We will find the most effective combination and study it in lots of models of DIPG through a network of labs. This combination will then be an excellent candidate to enter a combination clinical trial.

 

In the past, the way we have finally started to cure previously incurable childhood cancers, like leukemia and neuroblastoma, is through treatment that combines different medicines and different types of treatment. Then, those treatments can be improved continuously to cure more and more patients. Our plan is that this project will mark the first combination treatment in DIPG that starts to truly make a difference in survival and quality of life for DIPG patients. We also hope it will lead to a transition through which new treatments, as they develop through cooperation around the world, are built onto the existing combination so that the survival curve for DIPG can start to rise just like we’ve seen for other childhood cancers.

Executive Summary

Hypothesis

 

We believe that the key to improving survival for DIPG patients, and an eventual cure, depends on developing effective combination therapy for the disease that addresses its unique biology, focal impact in the pons, and spread throughout the central nervous system (CNS). This proposal builds on our previous work through the Cure Starts Now through which we built and studied models of components of this treatment. We determined that adding craniospinal radiation (CSI) to focal radiation therapy (RT) to the pons controls DIPG’s metastatic spread. We also found that, while systemic chemotherapy is able to reach DIPG tissue in patients, convection-enhanced delivery (CED) of chemotherapy directly to the pons can do so at higher concentrations. We know from clinical and preclinical studies, however, that neither radiation (focal and/or CSI) nor chemotherapy (systemic and/or CED) in adequate for long-term disease control. Based on our prior and preliminary findings, we hypothesize that combination treatment in three ways (RT/chemotherapy, focal/craniospinal treatment, and cytotoxic/targeted chemotherapy mechanisms) will achieve long-term survival in DIPG.

 

Goals

 

The most important result of our work will be to determine the optimal combination of radiation (both focal to the pons and CSI) and chemotherapy medicines (both systemic to target the whole CNS, and CED to increase delivery to the pons) to improve survival in patient-derived models of DIPG. This will involve studying not only overall combinations but the timing and sequence of treatments. We will work in parallel with the CONNECT Consortium’s preclinical (Dr. Chris Jones) and clinical (Dr. Maryam Fouladi) components to broaden the study of this approach across other DIPG models, and to develop a combination clinical trial to test our approach in patients. Along the way, we will determine answers to two critical questions in developing this treatment approach: Is DIPG metastatic from the time of diagnosis, and can standard (cytotoxic) chemotherapy be part of effective DIPG treatment after all of its failures?

 

By the end of this funding period, we expect to have a well-validated, effective combination treatment approach for DIPG that is progressing toward a clinical trial. We hope this will establish a new approach to DIPG that has enabled crucial advances in other previously incurable childhood cancers: to move away from separate trials of individual therapies and instead build on increasingly effective combinations toward long-term, high quality survival for patients.

 

Background

 

Focal RT is currently the only standard treatment of DIPG, although the disease clearly spreads throughout the CNS during the course of disease and is likely metastatic at diagnosis. Radiation overall is insufficient to control DIPG. Chemotherapy delivered systemically (oral or IV) has never been demonstrated effective in DIPG despite hundreds of clinical trials, although my lab has now shown that it can reach DIPG tissue in patients adequately for potential therapeutic benefit. Early evidence from the use of CED directly into the tumor shows potentially improved local tumor control and prolonged survival, but these patients then often die of metastatic disease. Therefore, by combining these four therapeutic modalities (focal RT+CSI, and systemic+CED chemotherapy), DIPG can potentially be controlled over the long term on both local and metastatic levels. Several medicines being tested in current or upcoming clinical trials address DIPG through different mechanisms and have shown preclinical or clinical signs of effectiveness through CED (panobinostat and carboplatin) or systemic (ribociclib, ONC201, and selinexor) routes. Since they are currently in individual trials and/or FDA-approved, these medicines offer the possibility of rapid incorporation into a combination clinical trial. Our preliminary data shows that CSI can limit metastatic disease in patient-derived xenograft (PDX) models of DIPG, and that CED delivers increased concentration of chemotherapy to the tumor. We have also found multiple effective combinations among the five drugs of interest and with RT.

 

Clinical Significance

 

Nearly all DIPG clinical trials and preclinical investigations have tested single modality treatments either alone or in combination with focal RT. Historically, however, major breakthroughs in treatment of previously incurable childhood cancers have necessitated multimodality approaches, for example in childhood acute lymphoblastic leukemia and high-risk neuroblastoma. We believe that our work will answer crucial questions and lead the way to a similar breakthrough in DIPG. The most crucial aspect of this project, therefore, is beginning this process of creating this combination for DIPG in a rational manner. We believe strongly that the backbone of focal+CSI RT and CED+systemic chemotherapy will be critical for achieving long-term survival. The drugs we consider for the initial chemotherapy combination have single agent safety data and preliminary clinical data in DIPG, and thus preclinical combination efficacy data is the only remaining step necessary for a combination trial that is a crucial next step in DIPG research. Having the necessary models in my lab, as well as key experience in translating my DIPG lab work to clinical trials, I believe I am ideally situated to accomplish this work.

 

Design and Methods

 

We will first test combinations of cytotoxic and targeted chemotherapeutic agents with radiation in a group of diverse patient-derived DIPG cell culture models, using agents with preclinical/clinical evidence of efficacy in DIPG, including panobinostat, ribociclib, ONC201, selinexor, and carboplatin. We will find effective and synergistic combinations across multiple cell lines and then conduct more advanced studies of multiple dose levels on promising combinations. We will then determine an optimal sequence of drugs in these successful combinations over longer-term cell culture studies. Next, we will use our orthotopic patient-derived xenograft (PDX) models of focal/metastatic DIPG to test the most promising combinations and sequences from cell culture studies. These preclinical trials will include the use of CED for agents with poor blood-brain barrier penetration (e.g. panobinostat) or low systemic efficacy (carboplatin). For these studies, we will use BT-245 and SU-SGC1 models of metastatic DIPG. We will first test the impact of CED chemotherapy and CSI on improving the efficacy of focal RT; we believe we will find prolonged local tumor control, but mice will now die of metastatic disease. Next, we will add systemic chemotherapy to RT and CED, which we believe with the optimal combination and schedule of drugs will achieve long-term local and metastatic tumor control. We will assess efficacy by survival and by imaging and pathologic assessment of disease, including study of microscopic metastases. We will use the CONNECT Preclinical Consortium to broaden our proposed combination treatment to additional models. We will also work in parallel with CONNECT to develop a clinical trial of combination therapy as we develop our preclinical work.

Description of Research Proposal

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Integer fermentum vestibulum lacinia. Duis id aliquam nibh, ut mattis leo. Nulla ac dui at sapien posuere facilisis ut quis ex. Aliquam vestibulum blandit tristique. Integer pretium dui ac nulla accumsan, et finibus velit euismod. Proin placerat, nunc eu sodales facilisis, tellus justo efficitur risus, non blandit diam nulla ac ligula. Aliquam ullamcorper quam leo, porttitor dictum ex tempor ac. Ut efficitur, justo et auctor volutpat, ex ex pulvinar est, sed consequat turpis leo nec ipsum. Nunc tempor, turpis ut ullamcorper tempor, dolor dui varius dui, et congue quam nisi vel nunc.

Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Donec faucibus, turpis sit amet maximus dapibus, sapien nisl bibendum turpis, pharetra commodo tellus libero vel nulla. Sed nec velit viverra, congue sapien et, gravida libero. Proin eget ante eget turpis egestas accumsan. Aliquam arcu nibh, aliquam rhoncus vulputate in, pellentesque at sem. Maecenas cursus tempus nibh id tempus. Mauris dolor sapien, lacinia sit amet condimentum at, dapibus eget lectus. Phasellus vel pellentesque ex. Nunc aliquam in ligula at tristique. In mollis suscipit felis eu finibus. Nullam non dignissim nibh, nec suscipit ex. Suspendisse tincidunt et mauris id finibus. Aliquam vehicula a sem quis venenatis.

Suspendisse leo odio, rutrum et viverra ut, consequat finibus enim. Vivamus dolor nisl, viverra eu egestas vel, blandit in nulla. Curabitur auctor purus non est volutpat bibendum. Proin fringilla magna sed metus maximus, in dictum neque suscipit. Sed ornare ut mi ut sodales. Nulla efficitur urna nunc, non molestie nunc egestas ut. Nunc arcu lorem, semper ut tincidunt ac, eleifend quis elit.

Sed at tortor et tortor tincidunt feugiat id in dui. Vivamus eget justo nisl. Aenean congue laoreet nisl a elementum. Nunc consectetur velit non ligula sollicitudin, quis eleifend urna sollicitudin. Sed tincidunt, nisl quis varius venenatis, dui massa condimentum tellus, sed sollicitudin diam magna mollis augue. Sed venenatis commodo purus id malesuada. Aenean volutpat elit vel gravida consectetur. Vestibulum diam quam, lacinia ac tortor eget, tincidunt dapibus dui. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Proin nisl leo, pretium sed arcu imperdiet, hendrerit sollicitudin sem. Duis non magna at nunc sagittis ullamcorper a id est. Maecenas cursus nisl in faucibus hendrerit.

Sed hendrerit vitae purus et tempor. Aenean vitae varius velit. Nullam aliquet ipsum elit. Mauris vestibulum purus et metus imperdiet, quis gravida eros pretium. Curabitur rutrum nunc vitae tincidunt condimentum. Aenean sit amet augue velit. Nunc tristique quis lorem id pharetra. Pellentesque sollicitudin, eros sed egestas rutrum, nulla nisl sodales elit, ut imperdiet nunc lectus sit amet nulla. Ut malesuada finibus libero. Curabitur mi dolor, sollicitudin quis bibendum quis, dictum sed enim.

Pellentesque nibh erat, egestas sit amet sagittis malesuada, rhoncus at neque. Mauris maximus commodo tortor, non egestas magna finibus vitae. Sed hendrerit nulla vel venenatis tempor. Suspendisse tristique tincidunt libero et placerat. Nam tincidunt condimentum lorem, vel pharetra est iaculis sed. Nullam ac tincidunt orci. Quisque pharetra ut sem sit amet aliquam. Phasellus risus libero, varius in condimentum vel, commodo id ipsum. Aliquam in metus cursus, mattis diam ut, aliquam magna. Suspendisse facilisis dui et orci varius, suscipit facilisis augue dapibus. In eget nibh ipsum. Suspendisse eget pharetra est, quis condimentum felis. Fusce scelerisque congue libero, sed aliquam mi elementum a. Etiam scelerisque ante non auctor porta. Nam eu nunc id ex finibus dictum. Praesent dui ex, dictum ac massa eget, rutrum gravida nisi.

Sed egestas arcu in dui euismod, eget faucibus massa iaculis. Etiam efficitur lectus et purus lobortis, ac blandit eros rutrum. Proin bibendum consectetur leo vel gravida. Etiam et ultricies sapien. Nam lacinia tellus erat, id facilisis est consequat et. Morbi quis risus in neque iaculis pharetra ut consectetur libero. Aenean feugiat tempor mi eu posuere.

Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.