Baskin Lab

The Targeted Cancer Treatment laboratory is the heart of the Peak Center research activities. It identifies and develops novel targets and delivery mechanisms to kill brain tumors and unravels the mechanisms that make these treatments work. The work from this laboratory feeds into the many other labs in the Peak Center who further develop and refine these novel treatments.

Projects include the development and refinement of Nano syringes that make individual injections into cancer cells, demonstration of the world’s first example of selective mitochondrial chemotherapy, and discovery of unique glucose transporters that exist in cancer cells only that can be utilized by novel molecules and poison the cancer cells’ energy supply.

Additional work is underway relating to differences in immune privilege in male and female cancer cells, and the development of serum biomarkers to diagnose brain tumors and monitor the success of therapy. 

PAM OBG: A first-generation monoamine oxidase B activated prodrug specifically targeting MGMT

MP-PT(IV) is a second-generation prodrug that is a MAOB prodrug that targets GBM mitochondria. This compound was synthesized in the laboratory by Dr. Sharpe and has been tested in vitro and in vivo. MP-PT(IV) combines the benefits of MAOB enzyme conversion into an active form as well as generation of cisplatin inside GBM cells causing targeted toxicity.

The efficacy of MP-PT(IV) was studied in vitro and in intracranial patient derived xenograft mouse model. This prodrug has also shown to potentiate existing standard of care therapy i.e. Temozolomide with radiation. 

A GLP grade synthesis is under work for this compound for scale-up and future use using combiflash for which Drs. Baskin and Sharpe have received TRI Award of 1.3 million by HMAI.

Epitope-targeted nanosyringes: peptidyl-coated nanovectors to bind to GBM cells receptors to create our drug-laden Trojan-horses

Nanosyringes are capable of delivering large amounts of drugs directly into the cancer cells with targeted surface epitopes. In the past, an antibody targeted as well as peptidyl targeted nanovector system was developed by Dr. Baskin and Dr. Sharpe. The two methods of delivering drugs in cancer cells were based on polyethylene glycosylated hydrophilic/hydrophobic carbon cluster (PEG-HCC) nanosyringes. These syringes can be filled with hydrophobic compounds such as chemotherapeutics and target them to cancer cells using antibody of peptides. 

Many in vitro and in vivo studies performed in the laboratories demonstrated the specificity of this drug delivery system by killing only brain tumor cells and not normal human astrocytes and neurons. In addition to delivery of chemotherapeutic drugs, this delivery mechanism was also used to inject drug pump inhibitors to fight drug resistance developing in cancer cells. 

Selected surface antigens on cancer cells are either not present or in very low levels in other body cells and therefore this mechanism gives an advantage of low off-site toxicity. This enables us to deliver higher concentrations of chemotherapy to cancer cells and no other tissues of the body, increasing the treatment efficacy with low toxicity. 

This model has been tested successfully in in vitro and intracranial mouse models with patient derived xenograft. Following interactions with the FDA personnel and reviewers recommendations the HCC core of the nanovector has been replaced. The Second generation of peptidyl-targeted nanosyringes that have high flexibility, allowing the delivery of both hydrophilic or hydrophobic payloads, including, but not restricted to, drugs, proteins, peptides, DNA, RNA and almost any combination of these. 

Martin Sharpe, PhD research focuses on novel targets, therapeutics and drug delivery systems aimed to find a cure glioblastoma multiforme (GBM). His approach is to find proteins, especially enzymes, transporters or surface antigens, which are much higher in the glioma than in a patient’s tissues, and use these for leverage.

PAM-OBG: Targeting Chemoresistance

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Nanosyringes

 

Targeted nanosyringes deliver their chemotherapeutic drug load to the surface of cancer cells. 

 

MITOCHONDRIAL Smart Bomb MP-Pt(IV) 

 

Our second generation mitochondrial ‘smart bomb’. Targets gliomal energy production and greatly increases the efficacy of conventional treatment.

Targeting the Sweet Tooth of Cancer

 

Inhibiting cell glycan synthesis with galactose analogues allows us to target glioma’s ‘sweet tooth’.

 

Nanosyringes for Selective Chemotherapy and to Poison Cancer Cell Drug Pumps In collaboration with Jim Tour and the Smalley Institute at Rice University we have made tiny nanosyringes that selectively deliver chemotherapy only to cancer cells.  We have been developing two major methods for treating cancer based on polyethylene glycosylated hydrophilic/hydrophobic carbon cluster (PEG-HCC) nanosyringes. We can fill these syringes with hydrophobic compounds, like the chemotherapeutic drugs docetaxel and vinblastine, and target them to the surface of the tumor by using either antibodies or attaching peptides to the nanosyringes PEG tendrils which bind to cell surface receptors that are found in high levels on the cancer cells.  We have demonstrated the ability to specifically target drug-filled syringes to the surface antigens of gliomal cells, killing them and sparing both human astrocytes and neurons. We have been able to increase the selective toxicity of chemotherapeutic drugs by using the nanosyringes to carry drug pump inhibitors. One of the major reasons for a cancer cell's drug resistance is that many cancer cells have high levels of drug pumps on their cell surface. These pumps can export chemotherapeutic drugs that diffuse inside the cell back outside. We fill nanosyringes, targeted to different cell surface antigens, with chemotherapeutic drugs or with inhibitors to the drug pumps which cancer cells use to give themselves resistance to these drugs. Cancer cells, with high levels of the target surface antigens, are covered with nanosyringes that release both drugs and drug pump inhibitors into the cell. Non-cancerous cells typically have low levels of one or more of the selected target antigen and will receive low, non-toxic, levels of a single chemotherapeutic or drug pump inhibitor. We can therefore achieve very high concentrations of chemotherapeutic drugs inside cancer cells, but very low levels elsewhere, thereby reducing the side effects of chemotherapy while increasing its efficacy.   

 

 

MP-MUS, a Novel Gliomal-specific, Mitochondrially-targeted Chemotherapeutic We have developed the very first successful selective mitochondrial chemotherapeutic agent for brain cancer.  We have designed, synthesized and tested in vitro and in vivo, a novel drug family formulated to specifically kill glioma. Gliomas are noted for their up-regulation of the mitochondrial enzyme Monoamine oxidase-B; this enzyme converts the uncharged MP-MUS pro-drug into the active, cationic drug P+MUS. P+MUS accumulates in the cells powerhouse, the mitochondria, destroying its small genome, mitochondrial DNA. The cancer cells attempt to overcome the toxicity by synthesizing more mitochondria, but in doing so increase their levels of Monoamine oxidase-B and thus make themselves more vulnerable to MP-MUS. Loss of mitochondria, and the release of mitochondrial apoptotic factors, cause gliomal cell death.

Omkar B. Ijare, Phd and research associate at the Kenneth R. Peak Brain and Pituitary Tumor Treatment Center is trying to develop methodologies to identify molecular markers of various subtypes of brain and pituitary tumors. Using a variant of conventional MRI it is possible to ‘peak under the hood’ and identify the major metabolites of a tumor mass, prior to treatment.

This can be used to inform physicians, prior to surgery, if they are dealing with a low grade tumor or a very aggressive tumor type. In many tumors this information only becomes available after pathology studies of an excised tumor, when the window for surgical intervention has passed.

Preliminary work involving the characterization of metabolic ‘fingerprints’ in pituitary tumors is already paying dividends. The pituitary tumors typically have high levels of brain metabolite, NAA. However, in tumors of the prolactinoma subtype, it has been shown that the NAA levels are very low. As prolactinoma tumors respond very well to chemotherapy with either cabergoline or bromocriptine, if we screen prolactinoma patients for NAA during the diagnostic workup, we should be able spare these patients from surgery. 

Another example of personalizing medicine comes from selecting a patient’s diet to perturb their tumor growth. Using a metabolic tracer, combined with MRI, can reveal the metabolism used by a particular tumor. Some tumors cannot grow well in the presence of high levels of circulating ketones, produced by ketogenic diet. However, in other tumor subtypes ketones are preferentially used as fuel and enhance tumor cancer cell growth. Knowing which type of tumor a patient has will allow us to issue rational dietary guidance.

Quantitative Magnetic Resonance can be used to examine cellular constituents and metabolites of tissue extracts and of tissues, like tumors, that have been freshly removed from patients. It is well known that altered metabolism is a hallmark of cancer and that metabolic fingerprints of aggressive tumors have been identified. 

Cancer cells are metabolically reprogrammed and depend on multiple nutrient energy sources to meet their cellular growth and proliferation activities. Here at Peak Center we employ cutting edge technology developed here to determine the fate of 13C-labeled nutrients. We give patients an intravenous infusion of labeled nutrients, such as sugars, ketones, fats or amino acids, just before the tumor is removed. Then identify how the cancer cells metabolize these compounds, in very high detail, allowing us to know the tumors sub-type as well as their strengths and weaknesses. This will allow us to answer question like “Would a ketogenic diet be beneficial for this patient?” or “Is this sub-type of tumor highly sensitive to a particular treatment regime?”

Quantitative Magnetic Resonance provides us with a personalized tumor metabolic roadmap, highlighting the cancer cells metabolic choke-points. We now sometimes know where to hit the cancer most effectively, and this is giving rise to completely new classes of drugs.