Functionalising drug development and treatment selection for solid tumour cancers

BioMarker Strategies introduces SnapPath®: a fluidics-based diagnostic system that enables automated and standardised ex vivo interrogation of live solid tumour cancers.

The pharmaceutical industry is rapidly moving beyond the development of single-target agents guided by single-biomarker tests to the development of drugs and combinations with complex mechanisms of action that will benefit from pathway-based diagnostics derived from an increasing understanding of the complex signal transduction network of living cells. The great promise of immunotherapy further complicates these challenges, particularly for solid tumour cancers.

In part, this is because currently available biomarker tests for solid tumours continue, primarily, to rely on dead, fixed tissue samples. Tests based on these static samples can reveal relevant mutations and guide general therapeutic approaches but are not particularly useful for understanding the mechanisms of acquired resistance. For this reason, they are not optimally predictive of individual tumour response to targeted treatments.

Live cells improve predictions

The dynamic information available only from live cells is required to understand initial response and the acquired resistance that too often develops in the treatment of cancer. This understanding is necessary for accurate prediction of individual response to targeted treatment of solid tumours.

Our patented SnapPath Cancer Diagnostics System is the only diagnostics system that can generate purified populations of live solid tumour cells from live, unfixed samples in an automated and standardised manner. The SnapPath system preserves the molecular integrity of these living cells for ex vivo exposure to targeted therapies and combinations. This enables generation of highly predictive biomarker tests we call ‘PathMAP® Functional Signaling Profiles’.

SnapPath is unique in its ability to automate and standardise functional ex vivo profiling to capture the dynamic and predictive signalling information available only from live solid tumour cells. Ex vivo biomarkers are dynamic molecular markers, such as phosphoproteins, that are evoked from live solid tumour cells after removal from the patient. Unlike static biomarkers detected from formalin-fixed tumour samples, ex vivo biomarkers enable true functional testing of cancer cells and can reveal important elements of tumour cell biology, including signal transduction circuitry.

Fast, automated, and versatile

SnapPath is a highly customisable, automated, fluidics-based cancer diagnostic system. It consists of a compact bench-top instrument and a single-use cartridge. It is technician-friendly, with a greatly simplified graphical user interface (GUI) that operates the script-controlled robotics. The system generates purified populations of live solid tumour cells from a fine needle aspiration biopsy, surgical excision or other live, unfixed tumour tissue sample. SnapPath is compatible with any solid tumour for which live tissue samples are available.

The process begins with the loading of live tissue samples onto the single-use cartridge, which is then snapped into place on the SnapPath instrument. The automated sample processing takes as little as 30 minutes and involves five steps:

  1. Dispersion;
  2. Enrichment;
  3. Distribution;
  4. Modulation; and
  5. Stabilisation.

In the dispersion step, the live solid tumour tissue samples are mechanically disaggregated into smaller, more homogeneous groups of living tumour cells. Following disaggregation, non-tumour cells such as red blood cells and white blood cells are removed from the sample using antibody-coated magnetic beads. The live cells are then distributed via automated fluidics into multiple test chambers for ex vivo modulation.

Following distribution into test wells on the cartridge, the live solid tumour cells are modulated by exposure to targeted therapies to evoke new biomarkers. The last automated step involves stabilisation of the modulated live cells using the method appropriate to the analytic technique of choice. The SnapPath system is agnostic to the type of analytic technology used.

An algorithm is then applied to the off-platform analytical result, yielding a Functional Signaling Profile which provides predictive information about drug response and resistance that cannot be obtained through DNA-based or RNA-based analysis of dead, fixed tissue samples.

Pipeline of biomarker tests developed in-house

The BioMarker Strategies business model is currently focused primarily on using our proprietary ex vivo diagnostics technology to provide research services to companies developing targeted drugs and combinations for the treatment of patients with solid tumour cancers. We expect to enter into our first commercial research services agreements this year.

We are also developing our own biomarker tests for metastatic melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and other solid tumours.

For metastatic melanoma, ‘PathMAP Melanoma’ is a functional predictive test to help select the optimal therapeutic approach for patients with advanced melanoma. PathMAP Melanoma utilises a panel of small molecule inhibitors, with an initial focus on molecules targeting BRAF and MEK. We will incorporate additional targets as they gain traction in clinical trials.

We are developing ‘PathMAP NSCLC’ as a functional predictive test for selection of optimal therapy for patients with NSCLC, the leading cause of cancer death in the US and much of the world. The approach is comparable to that used in our PathMAP Melanoma efforts but with additional targets, including epidermal growth factor receptor (EGFR). The majority of NSCLC patients are considered biomarker-negative for small molecule inhibitors, but it is clear that sub-populations of these patients can respond to therapy. Our feasibility data indicate that PathMAP Functional Signaling Profiles can help identify EGFR wild-type patients who may respond to EGFR inhibitors.

For HNSCC, the sixth leading cause of cancer worldwide, we are developing a pathway-based predictive test for response to cetuximab. This EGFR inhibitor was the first FDA-approved molecularly targeted agent for HNSCC but yields responses in only ~13% of patients. As additional therapies are approved in HNSCC, selection methods will become even more important.

We also plan to develop additional proof-of-concept data in other solid tumours, including breast, colon, pancreas, and others.

Personalised immuno-oncology platform

Immunotherapy targets cancer cells by boosting the immune system and has the potential to provide significant benefits to cancer patients. The three main challenges that persist are:

  1. The low objective response rate of 10-30% among patients receiving a single-agent immunotherapy;
  2. The selection of agents to combine with immunotherapy; and
  3. The emergence of mechanisms of resistance in patients who initially respond.

Predictive and therapeutic strategies for overcoming resistance and improving patient outcomes shape the immuno-oncology landscape for personalised medicine. With the increasing number of cancer therapy options and potential combinations, biomarker-based therapy selection becomes an indispensable tool in helping ensure that each patient receives the optimal ratio of therapeutic benefit to risk.

At BioMarker Strategies, we are making progress toward understanding with greater clarity why only a subset of patients responds to immunotherapy, and what measures could empower a robust immune response in patients who do not currently respond. We are working on biomarker-based selection to identify optimal responders, and we are also working to develop additive/synergistic options that may improve response rates and help avoid toxicity issues associated with immunotherapy.

Tumour heterogeneity is a major challenge in making informed decisions on the optimal therapeutic approach. SnapPath processing of solid tumours allows for a more complete functional profiling to capture and facilitate understanding of tumour heterogeneity. SnapPath processing of tumour samples also avoids inappropriate tissue dissociation that can degrade surface molecules, lead to alteration in the composition of cell sub-populations, and cause analytical bias that can confound outcomes and conclusions.

SnapPath’s ability to facilitate monitoring of both intrinsic and extrinsic aspects of tumour pathways, as well as the tumour microenvironment, makes the SnapPath system very well suited as a personalised immuno-oncology platform. By employing a fully optimised SnapPath method, high-quality single-cell suspensions can be obtained even from very small tissue samples, typical of clinical biopsies, for designing regimens for personalised tumour therapies, based on tumour heterogeneity in individual patients.

The BioMarker Strategies mission

Our mission is to help make personalised medicine more of a reality for patients with solid tumour cancers by providing powerful new molecular tools and research services to guide targeted drug development and personalised treatment selection.

 

Jerry Parrott

President and CEO

Biomarker Strategies, LLC

+1 301 917 9005

jparrott@biomarkerstrategies.com

http://www.biomarkerstrategies.com/

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