The group held a conference calls on July 18, Aug. 8, and Oct. 3. The next call is scheduled for Nov. 14.

July 18: Mr. Dhal demonstrated an AI-driven molecular docking platform he developed to support drug repurposing for diseases with limited treatment options. The software sources protein structures of a given target disease from databases such as the Protein Data Bank, identifies optimal binding sites, and enables high-throughput screening of small molecules. It incorporates AI models trained on biochemical data to evaluate and generate candidate compounds, iteratively optimizing selections until a target binding affinity is achieved. By integrating machine learning with traditional docking methods, the platform addresses limitations such as receptor rigidity to improve predictive accuracy and ADMET analysis. The demonstration focused on Pseudomyxoma Peritonei (PMP) and identified promising repurposing candidates for further translational investigation.

Mr Dhal also outlined his efforts to secure funding for his ongoing research and shared progress in establishing academic, commercial, and collaborative partnerships for the development of TRAABA24.

Dr. Metcalf discussed the ACPMP Research Foundation Changemaker Grant Program. The Changemaker Grant Program is intended to support scientific, clinical, or translational research studies—focused on appendix cancer or pseudomyxoma peritonei (PMP) of appendiceal origin—with the highest potential to ultimately impact patients or change our knowledge in appendiceal cancers to provide answers about this rare disease that will help to advance treatments for appendiceal cancer patients. Dr. Metcalf discussed why she thinks that the best approach to determining a bacterial cause of PMP would involve studying appendices rather than PMP tumors which occur downstream form the appendix lesion. In particular she is interested in using digital PCR on appendix specimens to study both Fusobacterium Nucleatum and Helicobacter pylori. If these bacteria are shown to be involved with PMP in the appendices of patients then the possibility of early detection of the disease through such things as fecal microbiome testing arises. In submitting the proposal, the goal would be to tie the bacterial study of potential bacterial causes of PMP to Mr. Dhal’s in silico research aimed at discovering new drug candidates for PMP. A discussion took place about how the various aspects of the research would be conducted and how the two research paths could be linked together. It is possible that cell culturing and in vivo animal testing can be done at Colorado State University and that Dr. Testerman could act as a consultant with staff there. The submission date for the Changemaker proposal is September 1. As a result, the group will hold our next conference call in early August to discuss our proposal.

Aug. 8: The conference call focused on preparing a proposal for the ACPMP Research Foundation Changemaker Grant Program. Proposals are due September 2. Dr. Metcalf started the discussion by mentioning that she had checked and culturing PMP cell lines can be done at Colorado State University. It may be necessary for Dr. Testerman to visit the University and share her PMP culturing expertise with them on her work. Dr. Metcalf envisions a 2-part proposal. One part would deal with a thorough study of fusobacterium nucleatum with the goal of answering some of the conflicting published information about its connection to PMP. She does not anticipate that culturing fusobacterium nucleatum itself would be required in the study. Part 2 would involve the in-silico research that Mr. Dhal has been undertaking to repurpose drugs to treat PMP. Mr. Dhal discussed research he has recently undertaken on cystic fibrosis where MUC2 mucin also plays a strong role in the disease. Dr. McAvoy raised the issue of whether it could be possible to tightly couple Mr. Dhal’s work with that in Dr. Metcalf’s lab, i.e. parts 1 and 2 of the proposal. Dr. Metcalf said that she will develop a draft of a proposal and put it on Google Docs for the group. She also mentioned that Qiangen has agreed to support the project. Mercy Medical will provide appendix specimens for the research and a letter of support for the proposal from Dr. Sardi will be sought.

Later on in August it was decided that a proposal would not be submitted for the Changemaker Grant. It was felt that our ideas did not coordinate enough together for a successful proposal to be written up. An alternative proposal will be considered and discussed during the next conference call in October.

Oct. 3: Dr. Metcalf discussed the letter she has prepared for submission to the ACPMP Foundation for their next PMP grant cycle. Dr. Metcalf is interested in studying Fusobacteria nucleatum and pks+ E. coli as well as other bacteria for their potential role in PMP.  Dr. Metcalf said that she would like to be able to get specimens for microbial study for the full range of disease conditions. She called this 3D sampling. She would like samples from appendices, and then downstream from tumors in the peritoneal cavity. A discussion was held about getting appendix specimens directly from the operating room. Ms. King discussed why this sampling would be difficult, since when the appendices are harvested, they are sent to pathology for analysis. At the pathology lab conditions are not sterile so contamination would be a real possibility. Dr. Metcalf asked whether it might be possible to get a mucin sample from an appendix that had a partial rupture and Ms. King said she will check. Ms. King also pointed out that many patients that are seen at Mercy have already had their appendices removed. The question of whether past appendiceal samples that were formalin fixed and paraffin embedded (FFPE) was discussed. The FFPE samples are those that have been returned after they were sent to pathology, so here again contamination is a potential issue. Dr. Mc Avoy asked whether it might be possible for Dr. Metcalf to approach local surgeons in Colorado and get appendix samples for inflamed and non-inflamed cases. These appendices could be compared for the presence of Fusobacteria nucleatum and pks+ E. coli. It was felt that this idea is worth looking into. Dr. Metcalf also asked whether it might be possible to take some swabs in the operating room at Mercy to assess potential contamination there. Ms. King said she would check. Ms. King mentioned that at Mercy they see all kinds of PMP cases. She noted that the mucin from the more aggressive forms of PM is different than that from the less aggressive forms. Mucin from the high-grade cancers tends to be harder while the low-grade cases produce softer mucin.

Mr. Dhal said that he had been travelling lately and he did not have much to report. However, he did report that he had investigated a protein called TMEM16A (also known as ANO1) that acts as a calcium activated chloride channel.
TMEM16A influences mucin synthesis and secretion, its implicated in diseases like Cystic Fibrosis as well as mucinous sub types of colon cancer. Celecoxib (Celebrex), a COX-2 inhibitor, is also a known inhibitor of TMEM16. The COX-2 pathway is implicated in micro satellite stable (MSS) colorectal cancer (through downstream effector molecules such as PGE2), and clinical trials are now underway exploring this. Mr. Dhal connected with Basingstoke recently and asked about their experience with Celecoxib.  He was surprised to learn it was a recommended maintenance therapy for PMP patients (under guidelines) until it was withdrawn from the market due to cardio toxicity reports in rheumatoid patients.   Mr. Dhal gave a reference to the use of celecoxib for treating PMP:

https://www.oncotarget.com/article/22455/text/

Dr. Svetlov asked whether he and Mr. Dhal could discuss the research that they have been carrying out on Mebendazole for treating PMP, and other drugs and how they should publish the research. The group agreed that this would be great.