Future Projects

Future Projects

On this page we describe some details about the various scientific projects we plan to undertake with funding from our fundraising campaign, and/or as new NIH and other grant proposals. We also offer these as potential projects with other researchers who want to bring their expertise and resources to collaborate.

Our two main areas for Future Projects include:

Primary brain tumors apparently grow for an average of 330 days before they are diagnosed (1). By that point they can already be 5-6 cm in diameter and so are scheduled for surgical resection. Additionally, LITT is currently only able to effectively heat up to ~3 cm, and so any improvements in early detection would be huge, and would offer a minimally invasive option to patients. Here we are considering at least two new options, Machine-Learning-Assisted Pre-Diagnosis and LDL Receptor Appearance 

Our approach here is to "make the drug look like the cancer's food" where again we use this natural pathway with specially designed prodrug particles being intravenously injected and crossing the blood brain barrier into the tumor. We are also considering  post-resection intra-cavity warming with i.v. LTSL-Dox,  and post resection intra-cavity drug delivery of a gelled-drug for diffusion into the remaining cancer cells that may escape the surgical resection. 

(1) Stensjøen, A.L., et al., When did the glioblastoma start growing, and how much time can be gained from surgical resection? A model based on the pattern of glioblastoma growth in vivo. Clinical Neurology and Neurosurgery, 2018. 170: p. 38-42. 

(2) Adekeye, A.O., D. Needham, and R. Rahman, Low-Density Lipoprotein Pathway Is a Ubiquitous Metabolic Vulnerability in High Grade Glioma Amenable for Nanotherapeutic Delivery. Pharmaceutics, 2023. 15(2): p. 599.

1.1 Machine-Learning-Assisted Early Diagnosis 

According to cancer.net,  there are certain signs such as headaches, altered personality, vision issues, nausea ....  that when taken in isolation, perhaps by a GP who is not looking for brain cancer diagnoses, often means brain cancer is overlooked at first pass.  However, if some predictions can be made from historical data, then an earlier diagnosis could possibly be made, and brain tumors caught earlier in their development. This could mean they are  caught small and and so amenable to low-invasive LITT + LTSL-Dox.of brain tumors using machine learning techniques to analyze historical data and help predict brain cancer occurrence; and utilizing the cancer's "need for food" and the LDL Receptor appearance as a new diagnostic approach for earliest diagnosis. 

Here we are looking to collaborate with AI software-engineers, epidemiologists and etiologists to draft out a plan for early diagnostic traits and generate an accessible system that can be disseminated to GPs and other care givers.

Anti-LDLR immunohistochemical analyses of paediatric high-grade glioma --from Adekeye et al (1).

(A) Positive liver control showing its normal level of LDLR expression;

((E) Anaplastic astrocytoma (AA, grade III) cells showing >50% LDLR expression;

((H) GBM (grade IV) cells with less with >50% LDLR expression.

All images were captured at 40  magnification; scale bars correspond to 100 micrometers in (A) and 50 micrometers in (E) and (H)

1.2 LDL Receptor Appearance as a Prognostic and Diagnostic Early Indicator?

Cancers feed on lipid and protein to support their anabolic requirements of growth, aggressiveness, and spread. To do this they feed on Lipoprotein particles from the blood stream and bring in these "food particles" into their cells by increasing the number of receptors on the cells and, we think, blood vessels. 

Earlier this year we published a new paper (1) that got written up in the press including Neuroscience News.  It showed widespread Low Density Lipoprotein Receptor (LDLR) expression in microscopic slides of adult and pediatric brain tumor samples.  The images to the left show how, while normal liver expresses receptors for these lipoprotein particles, both paediatric  Astrocytoma and GMB tumors are loaded with increased density of the receptors around all the blood vessels (brown coloration associated with detection-antibodies that bind to them).  

Thus, in a new realization, this feeding mechanism could enable a new diagnostic tool, where the appearance of the "food-receptors" is identified as soon as the tumors start expressing them, thereby catching them earlier in their development, and could be especially important for metastatic tumors if they can be shown to also over-express these receptors.

Here we are looking to team up with molecular diagnostic labs, with probably antibody-radio-imaging capabilities to generate LDLR-radio-labelled PET or SPECT imageable antibodies that can detect the up-regulation of LDLRs, that bring in the cancer's food, and so detect the cancers as they start their initial growth.

(1)  Adekeye, A.O., D. Needham, and R. Rahman, Low-Density Lipoprotein Pathway Is a Ubiquitous Metabolic Vulnerability in High Grade Glioma Amenable for Nanotherapeutic Delivery. Pharmaceutics, 2023. 15(2): p. 599.

2. Therapeutics: New Drug Delivery  Projects 

LDLR-peptide targeted Niclosamide Stearate Prodrug Therapeutic (NSPT) that would bind to the LDL Receptors on the Blood Brain Barrier

LDLR-peptide targeted NSPTs bind to and cross the Blood Tumor Barrier (Adapted from Zhang et al) (5).

Prodrug NSPTs are delivered at least to the peri-vascular niche where the most aggressive tumor cells reside as determined by Calabrese et al (4).

2.1 Make the Drug Look Like the Cancer's Food

This same up-regulation of Low Density and Very Low Density Lipoproteins (LDLs and VLDLs) are made in the liver and circulate in the blood stream around the body to support normal nutritional tissue requirements.  As above, it seems that many if not all cancers need these particles to support their metabolic reprogramming. Given this propensity to feed on natural LDL and VLDL nanoparticles from the blood stream, David, in his Niels Bohr Professorship in Denmark (2013-2020) and then with colleagues at Duke University have been exploring if and to what extent we could deliver anti-cancer drugs to tumors by "making the drug look like the cancer's food",

This approach has already  has shown promise using specially designed prodrug therapeutic particles in a mouse model of lung metastatic osteosarcoma (1) and has actually cured three dogs in a small feasibility canine trial (2) that would otherwise have succumbed to lung metastatic disease. This, "Trojan Horse approach" was featured in a @scienceft.engineering4000 2021 media video.  (Prof. David Needham fights cancer with his Trojan Horse).

While these particles may well accumulate in "regular" tumors by simply leaking out of the blood stream, in the brain tumor setting, it seems the blood brain barrier is so tight that there are no gaps big enough for such transport.  However, here, the brain tumor's vasculature facilitates the uptake of these all-important Lipoproteins by shuttling them across the blood vessel lining into the tumor itself.  And so we envision a project where we modify the already established prodrug therapeutic particles to utilize this brain-specific crossing-mechanism, and so deliver therapeutics that would not normally cross the BBB but do so now via this trojan horse approach.

Here we would like to collaborate with pharmaceutics labs that can fabricate the nanoparticles to our existing formulation and preclinical labs for initial cell and animal testing.

(1) Reddy, G., B., et al., Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) shows efficacy against Osteosarcoma. Molecular Cancer Therapeutics, 2020. 19(7): p. 1448.

(2) Manuscripts in preparation

(3) Zhang, Z. and C. Zhan, 5 - Receptor-mediated transportation through BBB, in Brain Targeted Drug Delivery System, H. Gao and X. Gao, Editors. 2019, Academic Press. p. 105-128.

(4) Calabrese, C., et al., A Perivascular Niche for Brain Tumor Stem Cells. Cancer Cell, 2007. 11(1): p. 69-82.

"Prof David Needham fights cancer with his Trojan Horse"

This, "Make the drug look like the cancer's food" or what might be called a "Trojan Horse" approach was featured in a @scienceft.engineering4000 2021 media video.  (Prof. David Needham fights cancer with his Trojan Horse)made by some media students while he was in Denmark on his Niels Bohr Professorship. The video is a n interesting juxtaposition of David's music (playing one of his other inventions --the "Snardhran" (A metal snare attached to the back of an Irish drum called a Bodhran) and his description of this new anti-cancer drug delivery approach.

2.2 Post Resection Intra-Cavity Warming with Intravenous LTSL-Dox

Primary GBM is usually, already, 5 - 6cm diameter upon initial diagnosis and so is rapidly scheduled for surgical resection (craniotomy).  Unfortunately, relapse is common due to even just a few remaining infiltrating tumor cells that were not able to be surgically removed.   Furthermore, as found by researchers at UNC Chapel Hill (1),  "removing a brain tumor causes any cancer left behind to grow 75 percent faster than the original tumor". 

Thus, in this project we thought we would expand on the LTSL-Dox application and bring it to an earlier intervention, -- to post resection treatment while still open. As shown in the schematic, with the cavity and parenchyma surface fresh and still accessible, infra-red heating could, in principle, warm at least 1mm (and possibly more depending on the wattage and wavelength),  into the remaining parenchyma.  This could then release doxorubicin from i.v.-LTSL-Dox in the blood vessels feeding those difficult- or impossible-to-remove cells, that are likely to generate a relapse.  

Here, we are looking to team up with hyperthermia engineers and clinicians to adapt and evaluate already-available torch-like  heating systems, and preclinical translational researchers who could test initial prototypes in animal studies.

(1) Okolie, O., et al., Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model. Neuro-Oncology, 2016. 18(12): p. 1622-1633.

2.3 Post Resection Intra-Cavity Drug Delivery

Following the work of Rahman et al, (1) this idea focuses on trying to  combat the disease at a stage of low residual tumor burden immediately post-surgery.  We propose a localized drug delivery system comprising a niclosamide formulation in a gel like matrix that is designed to be administered directly into brain parenchyma adjacent to the surgical cavity.   The idea is that the drug could diffuse into the un-resected parenchyma and reach and treat residual cells remaining, that are a source for relapse.  

This project requires detailed analyses and in vivo measurement of drug transport as a function of the particular parenchyma and tumor tissue architecture, and drug properties including, solubility, hydrophobicity, and membrane partitioning.  And so here we are looking to collaborate with transport engineers and pharmaceutical scientists, as well as preclinical labs to test this niclosamide formulation and also a range of drugs and scaffolds.

(1) McCrorie, P., et al., Etoposide and olaparib polymer-coated nanoparticles within a bioadhesive sprayable hydrogel for post-surgical localised delivery to brain tumours. Eur J Pharm Biopharm, 2020. 157: p. 108-120.