Leptomeningeal Metastasis - confronting an old problem with new technology: the Promise of Biosimulation

Leptomeningeal metastasis, also known as malignant meningitis and referred to as “Lepto” or “LMD” amongst oncologists, is a life-threatening complication of cancers which have spread to the meningeal lining of the brain and spinal cord. LMD can come from cancers arising in the brain or elsewhere in the body and is relatively uncommon, arising in 3 to 5% of patients with common metastatic malignancies like lung cancer, breast cancer, and melanoma. In patients with diffuse large cell lymphoma (DLBCL) and acute lymphoblastic leukemia, the odds of meningeal spread are already high at diagnosis and treatment is administered pre-emptively to effect cure.

Historically, diagnosing LMD has been challenging and traditionally requires the demonstration of malignant cells in the spinal fluid, i.e., a positive cytology, obtained from a symptomatic patient. Nowadays high-resolution MRI scanners find many more cases with lower disease burdens, thus increasing the apparent incidence but also discovering patients earlier in the course of disease and improving the opportunity for meaningful intervention.

Given the difficulty most drugs have difficulty crossing the blood brain barrier (BBB), an Omaya reservoir or port is placed on the scalp that permits injection of chemotherapy directly into the ventricular system that bathes the brain with spinal fluid, thus obviating the need for repeated lumbar puncture (i.e., spinal tap) to administer treatment. By using the Omaya, intrathecal (i.t.) chemotherapy is injected directly into the spinal fluid and can reduce neurologic symptoms and convert an immediately fatal course of weeks into 2 to 4-month median survival. Thus, while LMD is an especially grim diagnosis, it need not be viewed as strictly untreatable, even as the benefits of treatment leave much room for improvement. When given to lymphoma and leukemia patients, i.t. chemotherapy is proven to enhance cure.

Any of 4 i.t. chemotherapy agents can be administered in this fashion: methotrexate, liposomal cytarabine, topotecan, and thiotepa. But which one of the four is best for a specific patient? Should topotecan or another agent replace standard methotrexate in DBLCL? On the other hand, proton beam craniospinal irradiation (CSI) has been shown to enhance survival. Given the uncommon nature of LMD, no study to determine optimal therapy has been undertaken. But these treatment options are not equally efficacious as the relative effectiveness of each approach varies in the population. In practice, the selection of i.t. chemotherapy depends solely upon the physician’s experience, comfort, and bias, or what passes for “clinical judgment.” Patients who live near a proton radiation center may be more likely to receive radiotherapy, skipping over the deliberation whether it constitutes the best treatment option available for the patient. Some oncologists choose to administer i.t. methotrexate only because they learned to do so in training 20 or 30 years ago and never ventured outside their comfort zone. Still other questions also remain unanswered by clinical trials such as:

• Which single chemotherapy agent would be most effective?
• Would a combination of agents give a superior result?
• If the patient progresses during one treatment, should one of the other drugs be recommended?
• Would co-administration of i.t. corticosteroid hydrocortisone enhance or hamper the effect of chemotherapy?
• What is the efficacy of radiation and does it make sense to refer that patient to a center specializing in proton CSI?

These are routine clinical conundrums that arise in the management of patients. Remarkably, these questions are easily addressed by biosimulation, the new technology that converts comprehensive genomic information into a network model of cancer depicting the cancer’s dependencies and vulnerabilities. The network is defined by aberrant signaling pathways that determine the fate of the cell by re-organizing the transcriptional drivers that function master regulators. Biosimulation not only models the hallmark behaviors of cancer but how specific treatment strategies interact with a specific patient’s unique disease network. The study of cancer with this new technology reveals cancer’s formidable mediators of aggressive behavior but also uncovers imbalances in the malignant network that can be exploited as therapeutic vulnerabilities, or Achilles’ heels. Hitting the cancer where it is most vulnerable brings disease control. On the other hand, the history of oncology teaches that attacking cancer where it is strongest and best defended is futile.

Chemotherapy and radiation do not overcome the mechanistic wisdom embedded in 5 million years of evolution, unless they are targeting a specific vulnerability in the cancer…

In fact, biosimulation can determine how individual drugs interact with a particular cancer’s network and to stratify which drugs are most effective, whether combinations are superior to single agents, address the role of radiation, and even address the fundamental question whether any treatment at all should be given or continued in the face progression. In some instances, biomarkers of treatment benefit for one treatment approach confer resistance for others. Biosimulation also identifies mechanisms of therapy resistance thus creating hypotheses for treatment approaches that could rescue an approach that would otherwise fail.

To address these needs and opportunities, Cellworks Group, Inc. developed Singula that evaluates LMD patients for which of the four i.t. chemotherapy drugs make most sense or whether any value accrues from combination treatment. The impact of radiation is also biosimulated, thus providing a methodology to justify the expense and inconvenience of proton CSI that involves travel and weeks of planning and treatment. For patients that have MGMT methylation tests on the tumor, temozolomide and lomustine can also be considered in the biosimulation. Singula also determines homologous recombination repair deficiency (HRD) that can occur without classic BRCA1 or BRCA2 aberrations to address the potential utility of PARP inhibitors that cross the BBB. For cases where Singula LMD™ finds no effective therapies, clinicians can consider ordering Ventura to look broadly whether other drugs such as HDAC inhibitors, MTOR inhibitors, oxidative stress targeting, or combinations of TKI’s would potentially be helpful or rescue the efficacy of one of the standard therapies.

Randomized clinical trials assess treatment efficacy in a population of individuals assumed to be the same for the sake of treatment. The goal is to declare a winner. In contrast, biosimulation assesses therapy according to the unique genomic aberrations present in an individual patient’s cancer. The goal of this precision medicine approach to personalize the treatment strategy based upon comprehensive genomic diagnosis. As such, biosimulation is a bedside technique for translational oncology, converting complex and often overwhelming genomic information into actionable and clinically relevant therapeutic choices to enhance patient outcomes.

Among the various strategies available, what appears as a zero-sum game in population-based clinical trials represents an unevenly distributed group of winners and losers. For therapies with diverse mechanisms of antitumor activity, finding the best strategy for a specific patient is ultimately an individual undertaking unrelated to the less meaningful enterprise of declaring a single winner for disease management.

Biosimulation is most effective when patients have had whole exome NGS that includes comprehensive copy number aberrations. Liquid biopsy obtaining circulating tumor DNA (ctDNA) directly from the spinal fluid will further optimize inputs to the biosimulation model that enhance prediction accuracy. MGMT methylation should be sought, especially for KRAS mutated cancers where temozolomide or nitrosoureas may have remarkable efficacy. Some companies are also developing assays for promoter methylation of tumor suppressor and DNA repair genes. For clinicians studying novel biomarkers including microRNA and gene expression profiling, Cellworks can also include these analytes in the biosimulation process.

For patients with LMD, the stakes are high as outcomes can be immediately devastating and/or fatal. Arguably, the risk of selecting the wrong therapy is higher for clinicians wearing the proverbial molecular blindfold. Biosimulation offers a breakthrough technology that removes the blindfold, identifies the most promising therapy, and holds promise for improving the results of treatment in a challenging clinical scenario. For payors, biosimulation also improves the clinical value from health care expenditures by avoiding therapies that are unlikely to benefit the patient and delivering the best therapy upfront.

Singula and Ventura are registered trademarks of Cellworks Group Inc., a computational biosimulation company. Dr. Castro is employed by Cellworks.